The racemic compound carvedilol is a multiple-action oral antihypertensive drug that exhibits both vasodilator and non-selective beta-adrenergic blocking activities. The effects of the levorotatory S-enantiomer [S(-)-CARV] are vasodilatation and beta-blockade. The R(+)-enantiomer [R(+)-CARV] is a pure vasodilating agent. Quantitative determination of the enantiomers in human plasma by HPLC was carried out after formation of diastereoisomers with the chiral reagent 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC). The pharmacokinetics of the enantiomers were studied following i.v. (12.5 mg in 1 h) and p.o. (50 mg) administration of racemic carvedilol in ten healthy male subjects according to a randomized crossover design. The AUCs of S(-)-CARV were significantly lower than those of R(+)-CARV after both i.v. and p.o. administration. The systemic clearance of the two enantiomers was significantly different, whereas half-lives and apparent distribution volumes were comparable. Following p.o. administration, the absolute bioavailability (31.1% and 15.1%, respectively) and maximal plasma concentrations of R(+)-CARV were twice those of S(-)-CARV. A similar difference was found in the half-lives. A close correlation existed between enantiomeric ratios after i.v. and after p.o. administration, demonstrating slight intraindividual variability. The preferential systemic clearance of the S(-)-enantiomer suggests stereoselective hepatic metabolism of carvedilol, becoming especially apparent after p.o. administration. The small intrasubject variability in enantiomer ratios indicates a relatively constant relation of beta-blockade to vasodilation during chronic treatment.

Ple 1053 (Azosemid) is a diuretic which resembles furosemide chemically and in its mode of action. When administered intravenously, Ple 1053 was approximately 5 times more potent on a weight basis than furosemide, its dose-response relationship was closer and the slope was steeper. After oral administration Ple 1053 and furosemide were approximately equal in potency. However, the effect of Azosemid in healthy subjects was relatively prolonged and abrupt peaks did not occur.

17 patients with severe digoxin intoxication were successfully treated with 320 to 480 mg Fab fragments of digoxin-specific IgG from sheep. The infusion period ranged between 0.5 and 7 h. Serum and urine concentrations of digoxin bound to Fab fragments, and in 11 cases unbound Fab fragments in serum, were determined during and after the infusion. The renal clearance of bound digoxin and therefore of the antibody was 13.6 ml/min. The median extrarenal clearance of the Fab fragments was 10.9 ml/min. The half-life of the serum concentrations starting at 12 h was 14.3 h, and the value was increased to 25.4 h when regression began at 24 h; the corresponding apparent distribution volumes were 25.9 and 541. These figures exceed the volume of the extracellular space and suggest intracellular penetration of the Fab fragments. The dosage of the antibody should be sufficiently high to bind digoxin in the most severe cases of poisoning. The maximum serum concentrations of bound antibody were 30 mg/l after 3 h and 20 mg/l after 5 h. A loading dose of 160 mg followed by an infusion of 0.5 mg/min was sufficient to absorb digoxin re-diffusing into the serum during the first 8 h. In some cases free digoxin reappeared in the serum 8-12 h after beginning the treatment. This might be prevented by infusing a further ampoule at a rate of 0.1 mg/min or less.

The total body clearance of recombinant human erythropoietin (rhEPO) calculated per kilogram of body weight increased in the order man = dog < rat << mouse. The differences disappeared or were reversed when clearance was expressed per square meter of body surface. There was no similar species difference in terminal half life. Total body clearance increased with the dose in dogs and mice, but not in rats. The bioavailability from a subcutaneous depot was 80% in dogs, 76% in rats, and 70% in mice. The absorption from the subcutaneous depot is rapid in rats and mice, but slow in dogs. The pharmacodynamic activity of rhEPO injected by both routes was compared in polycythemic mice. The equipotent doses were 2.44 times higher with intravenous than with subcutaneous injection. Taking into account the bioavailability of 70% from a subcutaneous depot, one obtains a potency ratio of 3.5 for absorbed subcutaneous versus intravenous rhEPO.

SummaryIn a randomized, single-blind, placebo-controlled, cross-over Phase-I study pharmacokinetic and hemostatic properties of BM 06.022 were investigated in seven healthy, male human volunteers. The novel recombinant plasminogen activator BM 06.022 consists of the kringle 2 domain and the protease domain of human t-PA and is unglycosylated due to its expression in Escherichia coli cells. Vehicle or 6 MU (= 10.4 mg) BM 06.022 was administered as a single i.v. bolus injection of 10 ml over 2 min. BM 06.022 was well tolerated. Fibrinogen levels and clotting times remained unchanged at baseline levels after 6 MU BM 06.022; plasminogen and α2-antiplasmin (collected on chloromethylketone) decreased maximally to 83 ± 1% and 64 ± 3%, respectively, of baseline. D-dimers and fibrinogen degradation products increased to 1,006 ± 234 ng/ml and 555 ± 155 ng/ml, respectively, after BM 06.022. Half-life of BM 06.022-activity was 11.2 ± 0.4 min and of antigen was 13.9 ± 0.7 min, followed by a terminal half-life only for antigen of 173 ± 33 min. Plasma clearance of BM 06.022 was 371 ± 13 ml/min for activity and 183 ± 15 ml/min for antigen. Thus, BM 06.022 is not fibrinogenolytic at 6 MU and is a fibrinolytic agent with a longer half-life than t-PA.