Dieter Lockner

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.

Uptake of free and DNA-bound daunorubicin and doxorubicin into human leukemic cells

SummaryLeukemic cells from seven patients with acute nonlymphoblastic leukemia and granulocytes, and mononuclear cells from three healthy controls were isolated by centrifugation on metrozoate-dextran. The intracellular accumulation of both the free and DNA-bound forms of daunorubicin and doxorubicin was studied in vitro. The uptake of unbound daunorubicin was higher than that of doxorubicin. At drug concentrations of 1.75 μM and higher the uptake of the free drugs was greater than that of the bound forms, but at lower drug concentrations the uptake was about the same. This could at least partly be explained by a greater dissociation of the DNA-drug complexes at lower drug concentrations. The uptake into normal leukocytes was of the same order of magnitude as that into leukemic cells. There was a great interindividual variation in the accumulation of both free and DNA-bound drugs in the cells from leukemic patients. This variation might be of importance for the prediction of individual sensitivity to the different drugs.

Comparison of daunorubicin and daunorubicin-DNA complex in the treatment of acute nonlymphoblastic leukemia

SummarySixty consecutive patients, 15–60 years old, with ANLL were divided randomly into three groups for induction treatment with one of the following regimens: R1, daunorubicin (DNR) 1.5 mg/kg on day 1+ARA-C 2 mg/kg body weight on days 1–5; R2, DNR 1.5 mg/kg on days 1 and 2+ARA-C 2 mg/kg on days 4–8; R3, DNR-DNA complex 1.5 mg/kg on days 1 and 2+ARA-C 2 mg/kg on days 4–8. Maintenance treatment consisted of monthly courses of DNA 1.5 mg/kg (R1, R2) or DNR-DNA 1.5 mg/kg (R3) combined with ARA-C 1 mg/kg on days 1–5, alternating with thioguanine 2 mg/kg PO on days 1–5 combined with ARA-C 1 mg/kg IV on days 1–5. Fourteen patients of 20 went into complete remission with R1, 13 of 18 with R2, and 15 of 22 with R3. The overall remission frequency was 70% and there was no significant difference between the different groups. The median time in first remission and the median survival time were 300 and 510 days, respectively, with R1; 335 and 495 days with R2; and 295 and 677 days with R3. There was no statistically significant difference between the groups treated according to the different regimens concerning the time in first remission. Survival was slightly better with R3 than with R1. Treatment with the DNR-DNA complex caused less pronounced thrombocytopenia and fewer ‘minor’ cardiac abnormalities than treatment with free DNR in the same dosage schedule.

Treatment of acute nonlymphoblastic leukemia in adults with daunorubicin-DNA complex: A preliminary report

SummaryForty-four adult patients under 60 years of age with acute nonlymphoblastic leukemia were randomized for induction treatment with one of the following three regimens: R 1 = courses of daunorubicin on day 1+ARA-C on days 1–5; R 2 = courses of daunorubicin on days 1 and 2+ARA-C on days 4–8; R 3 = courses of daunorubicin-DNA complex on days 1–2+ ARA-C on days 4–8.Out of 14 patients, 9 went into remission on R 1, 6 out of 14 on R 2, and 8 out of 16 on R 3. The preliminary results suggest that daunorubicin-DNA complex has the same efficacy for inducing remission as daunorubicin alone, if the same time intervals and dosages are used.

Electrical impedance and erythrocyte sedimentation rate (ESR) of blood

The electrical impedance of blood is primarily determined by plasma resistance Rp, cell interior resistance Ri, and cell membrane capacitance Cm. These impedance parameters were measured for 62 samples with various erythrocyte sedimentation rates (ESR = 1-150 mm/h). A formula for estimating ESR by Rp and Cm was obtained by linear regression as: In (ESR) = 10.16-0.016 x f0, (r = 0.974, P < 0.001), where f0 = 10(9)/(2 pi.Rp100.Cm100) defined as the effective characteristic frequency in kHz, Rp100 = Rp/h in omega cm, Cm100 = Cm/h in pF/cm, h is the haematocrit in decimal. The 95% confidence intervals for the coefficients in the above equation were 9.73 to 10.59 and -0.017 to -0.015. The origin of the association was found reasonable since factors increasing the ESR, i.e., the concentration of some plasma proteins and the size of the blood cells, also elevate the capacitance. The results imply that the impedance measurement might be an alternative method for fast determination of the ESR.

Reducing the cardiotoxicity of anthracyclines by complex-bindin to DNA

Three patients with acute myeloblastic leukemia received high doses of daunorubicin, first in the free form and later as complex with DNA. Two of the patients also received doxorubicin‐DNA. Two patients showed symptoms of cardiotoxicity with signs of congestive heart failure after cumulative doses of 910 and 250 mg of noncomplexed daunorubicin/m2 body surface area, respectively. Thereafter they tolerated daunorubicin‐DNA complex up to total doses of 1430 mg and 1200 mg daunorubicin/m2, respectively, with no further signs of cardiotoxicity. One of them entered another complete remission after therapy with the complex. The third patient had received 820 mg daunorubicin/m2 and was in his second relapse when he was switched to daunorubicin‐DNA complex. A new remission was induced and the patient received a total daunorubicin dose of 1480 mg/m2 with no clinical signs of cardiotoxicity. However, a cardiac biopsy showed minor myocardial changes, which could have been due to daunorubicin. During a third relapse the patient received 270 mg/m2 doxorubicin‐DNA. At autopsy still only minor signs of cardiomyopathy were seen. Thus, complex‐binding of anthracyclines with the DNA appears to enhance the usefulness of these drugs in the treatment of patients with leukemia. Cancer 48:1531‐1534, 1981.

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.

Thrombolysis and fibrinolytic parameters during heparin treatment of deep vein thrombosis

Thirty-nine patients with symptomatic, venographically verified deep vein thrombosis (DVT) were studied during treatment with heparin in order to investigate the correlation between the venographic changes and parameters of heparin therapy or fibrinolytic components. Venograms were scored with a 40-grade scale, and after one week a significant improvement with an average reduction of the thrombi of 17% was observed. No statistically significant correlation was found between reduction of thrombus size and duration of heparin treatment, total amount of heparin administered, mean levels of APTT, plasmin-alpha 2-antiplasmin complex (PAP), tissue plasminogen activator (t-PA) antigen or t-PA-inhibitor. Only a short history of the thrombus was significantly correlated to thrombolysis. The concentrations of PAP and t-PA-inhibitor were not influenced, while that of t-PA antigen showed a significant increase during heparin infusion. Even if statistically significant correlations were not obtained, the patients with pronounced thrombolytic effect had high PAP-levels. Furthermore, patients with high t-PA-inhibitor levels had no lysis. The results suggest, that also other factors than plasminogen dependent fibrinolysis are of importance for the thrombolytic effect.