Eva Törnebohm

Low molecular weight heparin (KABI 2165, Fragmin): pharmacokinetics after intravenous and subcutaneous administration in human volunteers

The pharmacokinetics of a low molecular weight heparin (LMWH) with a mean mw of 4000-6000 D (KABI 2165, Fragmin) was studied in 6 healthy volunteers after intravenous (iv) and subcutaneous (sc) administration of 120 U (anti FXa)/kg. The half-life in plasma of the anti FXa activity after iv injection was 119 +/- 17 min, the volume of distribution (Vd) 3.4 +/- 0.5 1 and the total clearence 20.5 +/- 2.5 ml/min. The maximal anti FXa activity determined 3 min after iv bolus injection amounted to 2.2 +/- 0.3 U (anti FXa)/ml with a corresponding increase of the APTT from 31 +/- 7 sec to 113 +/- 35 sec. The elimination of the anti FXa activity was a monoexponential first order process. After sc administration the plasma half-life of the anti FXa activity was longer than after iv injection, 228 +/- 40 min, corresponding to the absorption rate thus found to be the rate limiting step. After sc administration the peak was reached after 4 hours (0.6 +/- 0.1 U (anti FXa)/ml; APTT increase 5 sec). The bioavailability after sc injection was calculated to be 87 +/- 6%. As a consequence of the high bioavailability and long T1/2 of the anti FXa activity, Fragmin administered sc seems to induce adequate levels of heparin-like activity making this regimen worth further investigation as an alternative for the treatment of deep venous thrombosis.

Fragmin once or twice daily subcutaneously in the treatment of deep venous thrombosis of the leg

In an open, randomised controlled study, 101 patients with phlebographically diagnosed deep vein thrombosis of the leg, not extending into more than two thirds of the femoral vein, were randomised to receive Fragmin (a low molecular weight heparin) administered subcutaneously either once or twice daily in doses of 200 U(anti-FXa)/kg/24h or 100 U(anti-FXa)/kg/12h respectively. Prior to Fragmin unfractionated heparin had been administered by continuous iv infusion for not longer than 24h. Warfarin was administered from the first treatment day. Fragmin was administered for at least 5 days or until the prothrombin complex had been within the therapeutic range for at least 2 days. Patients were kept in bed for the first day but thereafter were ambulant. Phlebography was repeated at 5-7 days. Comparison of the phlebograms revealed a similar improvement (reduction in Marder score) in both groups. There were 5 cases of bleeding: 1 major and 3 minor in the twice daily group and 1 minor bleed in the once daily group. There were no cases of clinical pulmonary embolism. It is concluded that Fragmin, administered as a single daily subcutaneous injection, is effective in the treatment of deep vein thromboses, and offers the advantages of reduced costs, despite higher price of the drug, including reduced nursing time.

Intravenous and Subcutaneous Administration of Fragmin in Deep Venous Thrombosis

54 patients with venographically verified deep venous thrombosis (DVT) were randomized to treatment with either intravenous infusions of 240 anti-Xa U/kg/12 h unfractionated heparin (UFH) or 240 or 120 anti-Xa U/kg/12 h of the low molecular weight heparin Fragmin. Repeated venographies showed improvement in 48% of the UFH-treated patients and 50 and 77%, respectively, in the Fragmin-treated patients. Progression was seen only in the UFH-treated patients and was observed in 11%. Two bleeding complications were seen in the Fragmin group in 2 patients receiving the very high dose of 240 anti-Xa U/kg/12 h. Anti-Xa activity in plasma and activated partial thromboplastin time (APTT) does not correlate in the Fragmin-treated patients. Fragmin was as effective as UFH in preventing the progress of thrombosis in DVT. In another study 120 anti-Xa U/kg Fragmin given subcutaneously 2 times daily to 13 patients with DVT resulted in adequate anti-Xa activity but with a tendency for accumulation of the Fragmin-induced activity. Subcutaneous injections of Fragmin 2 times daily also appears to prevent the progression of thrombosis effectively.

Pharmacokinetics of Intravenously and Subcutaneously Administered Fragmin in Healthy Volunteers

Studies in 8 healthy volunteers showed that the low molecular weight heparin Fragmin KabiVitrum is eliminated according to first order kinetics without dose dependency after intravenous injection of doses between 40 and 120 anti-Xa U/kg. Fragmin remains in the circulation more than twice as long as unfractionated heparin (UFH). Fragmin administered subcutaneously has a bioavailability which is much greater than that of UFH. Fragmin administered subcutaneously twice a day results in a significant anti-Xa activity and provides an alternative to intravenous infusions.

A pilot study; desmopressin (DDAVP) in the treatment of deep venous thrombosis

In a pilot study on 9 patients with acute deep venous thrombosis of the leg the fibrinolytic response and the possible thrombolytic effect of desmopressin (DDAVP), when given supplementary to standard heparin treatment, was examined. Six injections of 0.3-0.4 microgram DDAVP/kg b.w. at 12 hours intervals were given. No serious side effects were observed. The fibrinolytic variables that followed showed that plasma levels of t-PA increased significantly and most pronounced after the first injection. Rephlebography 4-7 days after hospitalization showed partial thrombolysis in 7 out of 9 patients. The phlebographic score according to Marder was reduced from 22.7 +/- 12.1 to 18.4 +/- 10.1 (p = 0.018), corresponding to a thrombus size reduction of 19%. No correlation between the level of the fibrinolytic variables measured and the degree of thrombolysis in the individual patients, could be demonstrated in this small number of patients.

Elastase Activity in Leukemic Cells

Elastase, a proteolytic enzyme which digests different clotting factors, has previously been isolated from monocytes, macrophages and granulocytes. In the present work, we have isolated leukemic cells from 1 patient with acute lymphoblastic leukemia (ALL) and from 6 patients with acute nonlymphoblastic leukemia. Detectable elastase activity was found in the cells from all patients with acute nonlymphoblastic leukemia and ranged from 0.016 to 0.619 mukat/l/micrograms DNA. The highest elastase activity was found in 1 patient with promyelocytic leukemia (M3), and no activity was found in the cells from the patient with ALL. It is possible that elastase-mediated proteolysis of coagulation factors is the mechanism responsible for bleeding complications which are frequent in M3.