Pharmacokinetics and tolerability of a new low molecular mass heparin (RO-11) in healthy volunteers--a dose-finding study within the therapeutical range.

This paper reports on the results of a Phase I, dose-finding study with a new low molecular mass heparin (LMMH) called RO-11. The study focused on pharmacokinetics, dose-effect relationship and on tolerability of three single subcutaneous (s.c.) doses within the therapeutical range. After the injection of 7,500, 9,000 and 12,500 anti-FXa i.u., the anti-FXa effect peaked between 3-6 h and showed a dose-dependent response. The absorption and elimination were first-order processes and the long half-life (> 5 h) kept constant after increasing doses. The compound was tolerated very well and no clinically relevant prolongation of APTT, prothrombin and thrombin clotting tests was observed. At the dose of 7,500 i.u., which corresponded to 110 anti-FXa i.u./Kg, RO-11 exerted anti-FXa effect for at least 18-20 h. We recommend using this dose in a single s.c. injection, to evaluate the efficacy and safety of RO-11 in the initial treatment of DVT or PE.

Bioavailability and pharmacokinetics of a new low molecular weight heparin (RO-11)--a three way cross-over study in healthy volunteers.

This study reports on the bioavailability and pharmaco kinetics of a new low molecular weight heparin (RO-11), with a mean molecular weight of 3,600-3,800 daltons. It was administered to 12 healthy individuals in an open, cross-over study. Each subject was randomly assigned to three experimental treatments: a) 30 mg by subcutaneous route, b) 60 mg subcutaneously and c) 60 mg intravenously, leaving a wash-out period of one week between treatments. The pharmacokinetic profile was calculated by means of the anti-FXa effect, measured on serial samples taken before and during the 24 h period after each treatment. The effects of the drug on global coagulation tests, Antithrombin-III levels, tissue-factor pathway inhibitor activity and anti-FIIa activity were also assessed. After the intravenous injection, a maximal anti-FXa effect of 1.30 +/- 0.18 IU/ml was measured at 0.05 h and was not measurable after 12 h. After the subcutaneous injection of 30 and 60 mg, the maximal anti-FXa effect (0.34 +/- 0.08 IU/ml and 0.54 +/- 0.06 IU/ml) was reached after 2-4 h, and was not measurable after 12-18 h. The magnitude of this effect was dose-dependent and the absorption and elimination processes followed a first-order pattern for every dose and route. RO-11 showed a biological half-life of about 5 h and a high subcutaneous bioavailability (96%).

Low levels of tissue factor pathway inhibitor (TFPI) in two out of three members of a family with thrombophilia.

We describe a family with severe thrombosis of early onset in two siblings and in their father. Low levels of TFPI were detected in the two siblings (50% and 45% respectively) but their parents have normal TFPI levels. All other hemostatic proteins associated with thrombophilia, as well as blood lipids were within the normal range. The release of TFPI, after heparin administration, was proportionally reduced in the two siblings as compared with controls. The study of this family does not permit to conclude that low levels of TFPI are responsible for their thrombophilia. In the future the study of more families with similar characteristics may allow to know the inheritance of TFPI and whether there is a causal relationship between low levels of TFPI and thrombosis.

The release of plasminogen activators (t-PA and u-PA) and plasminogen activator inhibitor (PAI-1) after venous stasis.

The aim of the present study was to compare plasma levels of urokinase-type plasminogen activator (u-PA), before and after 20 min of venous stasis, with those of tissue-type plasminogen activator (t-PA), type 1 plasminogen activator inhibitor (PAI-1) and t-PA/PAI-1 complexes, to determine whether both plasminogen activators and their inhibitor respond similarly to the same stimulus. We studied 36 patients with recurrent venous thrombosis in whom no coagulation defects predisposing them to thrombosis had been detected (mean age 38.2 years, range 15-70 years). Twenty healthy individuals (mean age 34.3 years, range 20-60 years) served as a control group. t-PA, PAI-1 and u-PA activity and antigen, as well as the t-PA/PAI-1 complex antigen, were measured before and after venous stasis. Post-stasis fibrinolytic parameters were corrected for the haemoconcentration which occurred during the venous occlusion test. Pathologically high PAI-1 levels (antigen and activity) were found in four out of 36 patients who were excluded from study. Functional and antigenic u-PA increased significantly after venous stasis when analysed as the absolute differences between paired samples (P less than 0.01). This increase in u-PA did not correlate with changes in t-PA or PAI-1 (r = 0.28 and r = 0.36 respectively). This leads us to suggest that different mechanisms relating to clearance and/or release from diverse sources might be involved in elevations of u-PA in response to a local endothelial stimulus. We conclude that venous stasis might not be the elective choice when evaluating 'bad responders' predisposed to thrombosis.

Tissue factor pathway inhibitor and anti-FXa kinetic profiles of a new low-molecular-mass heparin, Bemiparin, at therapeutic subcutaneous doses.

Low-molecular-mass heparins (LMMHs) exert an anti-FXa effect through antithrombin III (ATIII) and tissue factor pathway inhibitor (TFPI) displaced from endothelium and lipoproteins. This global anti-FXa potency is specific for different compounds. Whether these effects have a similar kinetic and duration is a matter of interest. We compared the kinetic profile of the TFPI effect (total and free) to the anti-FXa amidolytic activity induced by therapeutic subcutaneous doses of a new LMMH, Bemiparin. The overall kinetics of the anti-FXa amidolytic activity and the TFPI effect were different, TFPI achieving a maximal effect earlier than the anti-FXa activity and completely disappearing before it. The anti-FXa amidolytic activity of Bemiparin followed a linear dose-response pattern. Neither total nor free TFPI was directly proportional to the dose. At therapeutic subcutaneous doses, Bemiparin exerted an anti-FXa effect through TFPI during the first 2 h, through both ATIII and TFPI during the following 8 h (range 2-10 h) and through ATIII during the last 8 h (range 10-18 h).

The effect of endogenous oestradiol levels on protein S concentration during a menstrual cycle and after GnRH analogues and gonadotropin therapy.

We studied two groups of females to investigate the effect of endogenous oestradiol levels on total and free protein S (tPS, fPS) plasma concentrations. One group (group I) consisted of 12 healthy volunteers who were studied throughout one menstrual cycle; the other group (group II) consisted of 16 young women who were treated with GnRH analogues and gonadotropins before undergoing in vitro fertilization. Neither tPS nor fPS varied significantly with respect to the physiological changes of oestradiol or to the very low and high levels of oestradiol, achieved after GnRH analogues suppression and gonadotropin stimulation. These results indicate that endogenous oestradiol does not affect PS concentration.