Interspecies pharmacokinetic comparisons and allometric scaling of napsagatran, a low molecular weight thrombin inhibitor.

The objective of this work was to assess the pharmacokinetics of napsagatran, a low molecular weight thrombin inhibitor, after intravenous administration in a variety of laboratory animals, and prospectively to help design the first pharmacokinetic studies in man. Napsagatran is actively excreted into the bile and urine of various species and pronounced species-differences in its pharmacokinetics are observed. It is, therefore, an interesting compound to use in tests of the limitations of presently available inter-species scaling methods. The present data suggest that allometric exponent values which are consistent with the values expected for physiological processes and small organic molecules are not necessarily associated with successful predictions in man when active transport processes are involved in the disposition of the compounds. For example, compared with the values observed in man, the clearance (CL), non-renal clearance (CL(nr)) and the volume of distribution at steady state (Vd(ss)) were over-predicted by 3-, 7- and 2-fold, respectively, by use of allometry. Of the species tested, the cynomolgus monkey seemed to be the most useful for predicting kinetics in man when the approach based on concentration-time transformations was used. Thus, for half-life (t(1/2)), CL and Vd(ss), the observed mean values of 1.7 h, 459 mL min(-1) and 24 L kg(-1) in man were very close to the values predicted from the cynomolgus monkey (1.7 h, 652 mL min(-1) and 22 L kg(-1), respectively). The results show that there are large inter-species differences for kidney and liver excretion of napsagatran. This is probably because of the involvement of active transport processes, which compromised the kinetic extrapolation from animal to man, although a more thorough investigation of the transporters involved in the disposition of napsagatran is necessary to enable better understanding of the species differences observed.

[Dangerous thrombocytopenia in thrombolytic therapy of venous thrombosis of the leg]. / Gefährliche Thrombozytopenie unter thrombolytischer Therapie einer Beinvenenthrombose.

Two days after 5 days heparin treatment of a superficial thrombophlebitis a 45 year old woman was admitted to hospital with an extended phlebothrombosis of a leg. Before starting thrombolytic treatment a bolus of 5000 U heparin followed by 1000 U/h was administered. During thrombolytic treatment with ultrahigh streptokinase the platelet count dropped from 172,000/microliter to 73,000 and 29,000/microliter. Thrombocytopenia was considered not to be a complication of thrombolytic therapy but by demonstrating heparin induced platelet antibodies to be due to a heparin-associated thrombocytopenia type II (HAT Type II).

Catalytic activity and transformation potential of v-Src require arginine 385 in the substrate binding pocket.

Tyrosine kinase are important mediators of signal transduction in eukaryotic cells. In order to better understand the mechanism of catalysis we studied a set of mutants of the prototype tyrosine kinase, the c-Src protein, a homologue of the Rous Sarcoma virus oncogene. Based on an X-ray structure of cAMP-dependent protein kinase (cAPK) we mutated an arginine residue conserved in subdomain VI of all known kinases to a non-charged residue. This residue coordinates phosphate of the autophosphorylation site located in subdomain VII of cAPK and this interaction has been proposed to be crucial for substrate binding. The mutant R385A of c-Src had low kinase activity towards exogenous substrates yet was able to autophosphorylate at tyrosine 416. When introduced into an activated v-src gene the R385A mutation totally blocked cell transformation. Our data suggest that the function of the conserved arginine 385 is to coordinate the phosphate of the autophosphorylation site and to provide in this way a stable template for substrate binding.

Duodenogastric reflux in the fasting dog: role of pylorus and duodenal motility.

A two-marker technique was used to determine duodenogastric reflux in fasting dogs with normal or surgically modified gastroduodenal junctions. All nine dogs had an esophagostomy for gastric marker perfusion. The duodenal marker was given via a duodenal fistula. In two dogs a Heineke-Mikulicz pyloroplasty was performed, and in four dogs extramucosal circular pylorectomy was performed in addition. The mean fasting duodenogastric reflux rate in dogs with a normal pylorus was 1.1 +/- 0.5 (SE) ml/10 min; after pyloroplasty it was 1.6 +/- 0.3 ml/10 min (P greater than 0.1), and after pylorectomy it was 1.5 +/- 0.4 ml/10 min (P greater than 0.1). Simultaneous intraduodenal manometry revealed no relation between the interdigestive myoelectric complex and reflux. The marker technique for the measurement of reflux was validated by pharmacologically induced reflux. Subcutaneous injection of 0.1 mg of apomorphine increased the reflux rate tenfold. A transpyloric tube increased reflux rate fivefold. It is concluded that, in the fasting dog, phenomena such as retropulsive peristalsis are determinants of duodenogastric reflux and not the presence or absence of the pylorus and normal interdigestive motility.