European Journal of Clinical Pharmacology

Beermann, Björn

doi: 10.1007/BF00560889pmid: N/A

228 5 5 1 1 Björn Beermann The Department of Medicine and the Clinical Pharmacology Laboratory, Serafimerlasarettet Stockholm Sweden Summary An aqueous solution of 3 H-Lanatoside C and polyethylene glycol (PEG, a nonabsorbable marker) were administered orally to five subjects. The ratio between the radioactivity per mg PEG of gastrointestinal aspirates and the test solution showed that 10–30 per cent of the label was absorbed in the duodenum and upper jejunum. The urinary recovery of 38 to 57 per cent of the radioactivity indicated additional uptake of label in more distal parts of the intestines. The biliary excretion of label during the first day was estimated to be about 10 per cent. The total gastrointestinal absorption of radioactivity was calculated to be 40–65 per cent. — Due to acid hydrolysis in the stomach, a minor amount of 3 H-Lanatoside C was transformed, mainly to compounds tentatively identified as 3 H-digoxigenin and 3 H-digoxigenin-monodigitoxoside. — The major labelled compounds in the urine and the bile after oral administration appeared to be 3 H-digoxin and 3 H-desgluco-Lanatoside C. In one subject, who received 3 H-Lanatoside C intravenously, most of the label was excreted unchanged. On incubation with fresh faeces, 3 H-Lanatoside C was rapidly converted to compounds tentatively identified as 3 H-desgluco-Lanatoside C and 3 H-digoxin

Beermann, B.; Hellström, K.; Rosén, A.; Werner, B.

doi: 10.1007/BF00560890pmid: N/A

228 5 5 1 1 B. Beermann K. Hellström A. Rosén B. Werner The Departments of Medicine and Surgery and the Clinical Pharmacological Laboratory, Serafimerlasarettet Stockholm Sweden Summary 3 H-digoxin and 3 H-digitoxin were given orally to two middle-aged women who had thoracic duct lymphatic drainage. The plasma levels and urinary excretion of radioactivity were essentially the same as in normal controls. The cumulative recovery of 3 H-digoxin and its metabolites in lymph collected for 3 days was 4 per cent; and the corresponding value after administration of 3 H-digitoxin was 20 per cent. It was concluded that only minor amounts of digoxin and digitoxin are absorbed through lymphatic pathways.

Lader, S.; Bye, A.; Marsden, P.

doi: 10.1007/BF00560891pmid: N/A

228 5 5 1 1 S. Lader A. Bye P. Marsden Department of Clinical Pharmacology Wellcome Foundation Limited Beckenham Kent England the Department of Medicine King's College Hospital Medical School London England Summary No significant differences were found between plasma digoxin concentrations in samples assayed by both radioimmunoassay and 86 Rb uptake. The mean plasma digoxin concentration in 27 patients on a stable maintenance dose of digoxin was 1.1±0.6 ng/ml, while that in a group of 12 patients with clinical evidence of full or overdigitalization was 2.2±0.6 ng/ml, which was significantly greater ( p <0.05).

Beermann, B.

doi: 10.1007/BF00560892pmid: N/A

228 5 5 1 1 B. Beermann Department of Medicine and the Clinical Pharmacology Laboratory, Serafimerlasarettet Stockholm Sweden Summary Methyldigoxin-12α- 3 H and the nonabsorbable marker polyethylene glycol (PEG) were administered orally to five healthy subjects. Comparison of the radioactivity per mg PEG in gastrointestinal aspirates and the test solution (A/T ratio) showed that approximately two thirds of the label had been absorbed during its passage through the duodenum and the upper jejunum. The urinary recovery of label was 68–85 per cent. There was evidence of biliary excretion of label, not exceeding 15 per cent during the first day. The total absorption of radioactivity amounted to 75–90 per cent. The uptake of label did not reflect the absorption of 3 H-methyldigoxin. Part of the 3 H-methyldigoxin was hydrolysed in the stomach, a reaction which resulted in the formation of labelled compounds tentatively identified as digoxigenin and its derivatives with one to three digitoxose moieties. — The major part of the urinary and biliary label appeared to be attached to methyldigoxin (26–60 per cent) and digoxin (31–59 per cent). The degree of demethylation was approximately the same after oral administration as after intravenous injection of 3 H-methyldigoxin in one subject.

Ohnhaus, E.; Spring, P.; Dettli, L.

doi: 10.1007/BF00560893pmid: N/A

228 5 5 1 1 E. E. Ohnhaus P. Spring L. Dettli Department of Experimental Therapeutics, Biological and Medical Research Division Sandoz Ltd. Basel Switzerland Department of Clinical Pharmacology Bürgerspital Basel Switzerland Summary The protein binding of digoxin in human serum was investigated using equilibrium dialysis and tritium-labelled digoxin. A constant protein bound fraction of about 30% was found over a wide range of concentrations of digoxin including therapeutic levels. Interpretation of the findings according to the law of mass-action showed an association constant K = 0.68·10 −5 l/mol; and, the number of binding sites, n → ∞, indicating an almost infinite apparent maximum binding capacity and a very small affinity of human serum proteins for digoxin.

Adolfsson, L.; Areskog, N.; Furberg, C.; Granath, A.; Zetterquist, S.

doi: 10.1007/BF00560894pmid: N/A

228 5 5 1 1 L. Adolfsson N. -H. Areskog C. Furberg A. Granath S. Zetterquist Departments of Clinical Physiology, Linköping, Boden and Danderyd Sweden Summary 23 male patients with coronary insufficiency on exertion underwent standardized work tests using a bicycle ergometer. In a double blind randomized trial they received oral doses of 2 mg pindolol (LB 46), 5 mg Isosorbidedinitrate (ISO), 2 mg pindolol + 5 mg isosorbidedinitrate (LBI 25) and a placebo. LBI 25, LB 46 and ISO all produced significant increases in the work performed before symptoms and signs appeared of coronary insufficiency. The mean increase in total work was: LBI 25 69%; LB 46 49%; and ISO 33%. The corresponding figures for work performed up to the time of appearance of ST-depression were: LBI 25 115%; LB 46 87%; and ISO 54%. A moderate synergism between ISO and LB 46 was found in 17 of the 23 patients. Tiredness in the legs during work was more common in patients taking beta-blocking agents. Nine patients complained of slight headache, mostly after LBI 25 and ISO.

Åblad, B.; Ervik, M.; Hallgren, J.; Johnsson, G.; Sölvell, L.

doi: 10.1007/BF00560895pmid: N/A

228 5 5 1 1 B. Åblad M. Ervik J. Hallgren G. Johnsson L. Sölvell Department of Pharmacology and Department of Pharmacy and Analytical Chemistry AB Hässle Göteborg Sweden Department of Medicine II Sahlgrenska Hospital Göteborg Sweden Summary The effects of alprenolol on heart rate and systolic blood pressure were studied in healthy subjects during standardized exercise on a bicycle ergometer. In one series of experiments, in which serum concentrations of alprenolol were also measured, the effects of single oral doses of 50, 100 and 200 mg of alprenolol and a placebo were compared by a double blind cross-over technique. In a second series of experiments 100 mg alprenolol was given four times in one day and the effect was followed for up to eighteen hours after the last dose. — Alprenolol diminished the expected increase in heart rate and systolic blood pressure during exercise. The reduction of exercise tachycardia in a given individual was linearly related to the logarithm of the dose or the serum concentration of alprenolol. The serum concentrations required for a given reduction of exercise tachycardia varied almost one hundred-fold amongst the subjects studied. The biological availability of alprenolol was dose-dependent, probably due to a limited capacity biotransformation of the drug before it entered the general circulation. After a single dose the serum level of alprenolol and its chronotropic effect diminished at a rate corresponding to an elimination half life of about two hours. This rate of elimination was consistent with that calculated from the results of the four dose study.

Krönig, B.; Fiegel, P.; Weihrauch, Th.; Höffler, D.; Jahnecke, J.; Arndt-Hanser, A.

doi: 10.1007/BF00560896pmid: N/A

228 5 5 1 1 B. Krönig P. Fiegel Th. Weihrauch D. Höffler J. Jahnecke A. Arndt-Hanser I. Medizinische Klinik and Poliklinik and Transfusionszentrale Johannes-Gutenberg-Universität Mainz F.R.G. Summary A case is reported in which a 36-year-old patient twice suffered a rapidly-developing severe reaction to intermittent rifampicin therapy. The symptoms were upper abdominal and back pain, nausea and shivering. Acute renal failure, thrombocytopenia, jaundice and haemolytic anaemia also developed. Aetiologically this was due to an immunopathological effect. This case was unusual in that all the previously observed reactions to rifampicin of an immunological aetiology occurred together, resulting in a marked leucocytosis with the presence of immature cells. It appears that the immediate administration of high-dose corticosteroids can favourably influence this condition. We consider that despite its greater risks daily treatment with rifampicin is to be preferred to discontinuous therapy because of its better tuberculostatic effect.

Vojvodić, V.; Maksimović, M.

doi: 10.1007/BF00560897pmid: N/A

228 5 5 1 1 V. B. Vojvodić M. Maksimović Department of Pharmacology and Toxicology Institute of Technical and Medical Protection Vojvode Stepe 445 Belgrade Yugoslavia Summary A dose of 1.0 g (10.0–14.0 mg/kg body weight) of pralidoxime mixed with various cholinolytics was given by i.m. injection to 29 healthy male subjects. A concentration of pralidoxime in blood of 4 µg/ml was reached after 5 to 10 min with all the mixtures and was maintained for about 1 to 2 h. The calculated half lives of pralidoxime in three groups of subjects were 62.2, 60.0 and 61.8 min., respectively. — The urinary excretions of pralidoxime during the first 4 h after the injections averaged 75.0, 79.6 and 69.6 per cent, respectively, of the total amount given. — The results are compared with published information about similar oximes.