Preclinical safety evaluation of low molecular weight heparin-deoxycholate conjugates as an oral anticoagulant.

The preclinical safety of a newly developed oral anticoagulant, the low molecular weight heparin-deoxycholate conjugate (OH09208), was evaluated by a comprehensive evaluating program in compliance with standard guidelines. The single dose oral toxicity study in rats receiving 2000 and 5000 mg kg(-1) of OH09208 did not reveal any mortality, unusual body weight changes or necropsy findings. The results of the 4-week oral toxicity study with a 4-week recovery program in rats receiving OH09208 in doses of 100, 300 and 1000 mg kg(-1) day(-1) did not reveal any mortality, or indicate any unusual clinical signs, or show any toxicokinetic relationships to the administration of OH09208. Although the increase in liver enzymes in one male dog treated with 300 mg kg(-1) day(-1) and one female dog treated with 1000 mg kg(-1) day(-1) could not be excluded from the effect of the test substance, no other toxicologically significant changes were observed in the 4-week oral toxicity study with a 4-week recovery in beagle dogs. Thus, while the no-observed-adverse-effect level value from the 4-week study in both male and female rats was 1000 mg kg(-1) day(-1), those from the 4-week study in male and female beagle dogs were 300 and 1000 mg kg(-1) day(-1), respectively. Furthermore, OH09208 did not induce anaphylactic reactions in guinea pigs, micronucleated bone marrow cells in male ICR mice, chromosomal aberration in Chinese hamster lung cell lines, bacterial reverse mutation, and any abnormalities in hERG current assay, mouse central nervous system and dog cardiovascular studies. Overall, there were no unexpected toxicities in this preclinical study that might have precluded the safe administration of OH09208 to humans.

Functionalized heparin-protamine based self-assembled nanocomplex for efficient anti-angiogenic therapy.

Angiogenesis is a key feature of cancer development, thus it is a good target for cancer therapy. However, drugs that have been designed to block angiogenesis mainly capture growth factors in circulation, resulting not only in the transient inhibition of tumor progression but also in producing undesirable side effects. Nanoparticular drug delivery systems, on the other hand, may help overcome such drawbacks and improve the efficacy of anti-angiogenic therapies by altering the biodistribution and pharmacokinetics, improving tumor targeting ability, and reducing side effects. In this light, we propose a new approach of anti-angiogenic therapy that combines strategies of long circulating, passive tumor targeting, and anti-angiogenesis efficacy using a new polyelectrolyte complex system that combines LHT7, a previously developed heparin-based angiogenesis inhibitor, with a protamine to form a self-assembling nanocomplex with a mean diameter of 200nm, which is effective for anti-angiogenesis therapy. At first, LHT7 was modified with polyethylene glycol (PEG). We observed that PEG-LHT7/protamine nanocomplex was stable in buffer and slowly dissociated in plasma (9% dissociation for 24h). Compared to the free form of PEG-LHT7, the mean residence time of PEG-LHT7/protamine nanocomplex was found higher (15.9h) with its increased accumulation in tumor. Most importantly, PEG-LHT7/protamine nanocomplex was diffused and extravasated through the dense collagen matrix of the tumor. Thus, the study describes a successful application of functionalized PEG-LHT/protamine nanocomplex that can inhibit angiogenesis with long circulating, passive targeting, and tumor extravasating ability.

Preliminary safety evaluation of a taurocholate-conjugated low-molecular-weight heparin derivative (LHT7): a potent angiogenesis inhibitor.

In our previous studies, taurocholic acid (TA)-conjugated low-molecular-weight heparin derivative (LHT7) has been proven to be a potent anti-angiogenic agent by demonstrated successful blockage capability of vascular endothelial growth factors (VEGF). Preliminary safety evaluations were conducted based on its mechanism of action and chemical behavior. For this purpose, acute toxicity study, and hematological and serological evaluations were carried out. Additionally, in order to evaluate mechanism-related side effects, both blood pressure and the occurrence of proteinuria were measured using a treatment regime of multiple high doses of LHT7 in a biodistribution study. LD50 values for LHT7 in female and male mice were 56.9 and 64.7 mg kg(-1) doses, respectively. There were no vital fluctuations in the serological and hematological parameters, except for the elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 100 and 200 mg kg(-1) doses of LHT7, representing vital changes in the liver function. Moreover, the results of mechanism-related studies showed that blood pressure at 50 mg kg(-1) did not change but showed elevated levels of protein in urine. In the biodistribution study, a slight accumulation of LHT7 in the kidney and the liver were observed at the 50 mg kg(-1) repeated dose owing to the presence of bile acid. No fatal damage was observed in this study; most observations were related to the chemical composition or the mechanism of action of the material.

Preparation and characterization of self-assembled nanoparticles based on low-molecular-weight heparin and stearylamine conjugates for controlled delivery of docetaxel.

Low-molecular-weight heparin (LMWH)-stearylamine (SA) conjugates (LHSA)-based self-assembled nanoparticles were prepared for intravenous delivery of docetaxel (DCT). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide were used as coupling agents for synthesis of LHSA conjugates. The physicochemical properties, in vitro antitumor efficacy, in vitro cellular uptake efficiency, in vivo antitumor efficacy, and in vivo pharmacokinetics of LHSA nanoparticles were investigated. The LHSA nanoparticles exhibited a spherical shape with a mean diameter of 140-180 nm and a negative surface charge. According to in vitro release and in vivo pharmacokinetic test results, the docetaxel-loaded LHSA5 (LMWH:SA =1:5) nanoparticles exhibited sustained drug release profiles. The blank LHSA nanoparticles demonstrated only an insignificant cytotoxicity in MCF-7 and MDAMB 231 human breast cancer cells; additionally, higher cellular uptake of coumarin 6 (C6) in MCF-7 and MDAMB 231 cells was observed in the LHSA5 nanoparticles group than that in the C6 solution group. The in vivo tumor growth inhibition efficacy of docetaxel-loaded LHSA5 nanoparticles was also significantly higher than the Taxotere-treated group in the MDAMB 231 tumor-xenografted mouse model. These results indicated that the LHSA5-based nanoparticles could be a promising anticancer drug delivery system.

M118--a rationally engineered low-molecular-weight heparin designed specifically for the treatment of acute coronary syndromes.

The initial choice of anticoagulant therapy administered in emergency departments for acute coronary syndromes (ACS) has important consequences for subsequent patient care, as neither unfractionated heparin (UFH) nor low-molecular-weight heparin (LMWH) are ideally suited for all potential clinical treatment pathways. UFH remains widely used for surgical interventions because of the ability to rapidly reverse its anticoagulant activity. However, the unpredictable pharmacokinetic profile of UFH presents safety issues, and the low subcutaneous bioavailability limits the utility of UFH for patients who are medically managed. LMWH has superior pharmacokinetic properties, but its anticoagulant activity cannot be effectively monitored or reversed during surgery. There is an unmet medical need for a baseline anticoagulant therapy that addresses these shortcomings while retaining the beneficial properties of both UFH and LMWH. We describe here M118, a novel LMWH designed specifically for use in the treatment of ACS. M118 shows broad anticoagulant activity, including potent activity against both factor Xa (~240 IU/mg) and thrombin (factor IIa; ~170 IU/mg), low polydispersity, high (78%) subcutaneous bioavailability in rabbits, and predictable subcutaneous and intravenous pharmacokinetics. Additionally, the anticoagulant activity of M118 is monitorable by standard coagulation assays and is reversible with protamine. M118 demonstrates superior activity to conventional LMWH in a rabbit model of abdominal arterial thrombosis without increasing bleeding risk, and is currently being evaluated in a phase II clinical trial evaluating efficacy and safety in patients undergoing percutaneous coronary intervention.

AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery--TREK: a dose-ranging study.

BACKGROUND: AVE5026 is a new hemisynthetic ultra-low-molecular-weight heparin, with a novel anti-thrombotic profile resulting from high anti-factor (F)Xa activity and residual anti-FIIa activity. AVE5026 is in clinical development for venous thromboembolism (VTE) prevention, a frequent complication after total knee replacement (TKR) surgery. OBJECTIVES: This study evaluated the dose-response of AVE5026 for the prevention of VTE in patients undergoing TKR surgery. PATIENTS/METHODS: In this parallel-group, double-blind, double-dummy study, 690 patients were randomized, and 678 treated with once-daily doses of AVE5026 (5, 10, 20, 40, or 60 mg) or enoxaparin 40 mg in the calibrator arm. The primary efficacy end point was VTE until post-operative day 11, defined as deep vein thrombosis (DVT) detected by bilateral venography, symptomatic DVT, non-fatal pulmonary embolism (PE) and VTE-related death. The primary safety outcome was the incidence of major bleeding. RESULTS: The primary efficacy outcome was assessed in 464 patients. There was a significant dose-response across the five AVE5026 groups for VTE prevention (P<0.0001), with the incidence of VTE ranging from 5.3% to 44.1% compared with 35.8% in the enoxaparin group and for proximal DVT (P=0.0002). Also, a significant dose-response for AVE5026 was seen for major bleeding (P=0.0231) and any bleeding (P=0.0003). Six patients in the AVE5026 groups, four in the 60 mg group, experienced major bleeding; none did in the enoxaparin group. CONCLUSIONS: The safety and efficacy results of this study suggest that a AVE5026 dose of between 20 and 40 mg presents an adequate benefit-to-risk ratio.

Inhalable large porous microspheres of low molecular weight heparin: in vitro and in vivo evaluation.

This study tests the feasibility of large porous particles as long-acting carriers for pulmonary delivery of low molecular weight heparin (LMWH). Microspheres were prepared with a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), by a double-emulsion-solvent-evaporation technique. The drug entrapment efficiencies of the microspheres were increased by modifying them with three different additivespolyethyleneimine (PEI), Span 60 and stearylamine. The resulting microspheres were evaluated for morphology, size, zeta potential, density, in vitro drug-release properties, cytotoxicity, and for pulmonary absorption in vivo. Scanning electron microscopic examination suggests that the porosity of the particles increased with the increase in aqueous volume fraction. The amount of aqueous volume fraction and the type of core-modifying agent added to the aqueous interior had varying degrees of effect on the size, density and aerodynamic diameter of the particles. When PEI was incorporated in the internal aqueous phase, the entrapment efficiency was increased from 16.22+/-1.32% to 54.82+/-2.79%. The amount of drug released in the initial burst phase and the release-rate constant for the core-modified microspheres were greater than those for the plain microspheres. After pulmonary administration, the half-life of the drug from the PEI- and stearylamine-modified microspheres was increased by 5- to 6-fold compared to the drug entrapped in plain microspheres. The viability of Calu-3 cells was not adversely affected when incubated with the microspheres. Overall, the data presented here suggest that the newly developed porous microspheres of LMWH have the potential to be used in a form deliverable by dry-powder inhaler as an alternative to multiple parenteral administrations of LMWH.

Toxicity screening after repeated dose of a newly developed oral heparin derivative in male cynomolgus monkeys.

Toxicity screening of a newly developed oral heparin derivative was carried out in twelve male cynomolgus monkeys (Macaca fascicularis), composed of three treatment and vehicle control groups. A newly orally active heparin derivative, developed by Seoul National University, was given to the treatment group at three doses with low (12.8 mg/kg), medium (89.6 mg/kg) and high (640 mg/kg) doses for 14 days. A treatment group did not show any change in body weights, hematological parameters (e.g., RBC, WBC, platelet, PDW, MPV, etc.) and serum biochemical parameters (e.g., AST, ALT, BUN, etc.) for 2 weeks compared with those of the vehicle control group. These findings indicated that the oral anticoagulant drug, a newly developed oral heparin derivative, did not have any toxic effect for 2 week in this study. The present study will be valuable in the proper interpretation for non-clinical study using cynomolgus monkeys in the development of a new drug of heparin derivative.

A newly developed oral heparin derivative for deep vein thrombosis: non-human primate study.

The development of orally active heparin will have tremendous clinical importance since it can be used to effectively prevent deep vein thrombosis (DVT) in a long-term chronic treatment. We developed in this study a new orally active heparin derivative (Db-LHD), which has heparin chemically conjugated with deoxycholic acid and DMSO molecules by secondary interactions. Db-LHD was prepared in the powder form in soft capsules. When we administered Db-LHD capsules to monkeys, its oral physiological availability was increased up to 16.6%. The maximum anti-FXa activity at 5 mg/kg of Db-LHD was more than twice the minimum effective anti-FXa activity (MEC, 0.1 IU/mL) for preventing DVT, and the anti-FXa activity in plasma was maintained for 10 h above the MEC in monkeys. Also, we evaluated anti-thrombogenic effect of Db-LHD in a rat thrombosis model. A subcutaneous administration of enoxaparin (100 IU/kg), which was the highest recommended dose for the prevention of venous thromboembolism, reduced thrombus formation by 38.9+/-14.2%. On the other hand, 5 mg/kg (425 IU/kg) of orally administered Db-LHD reduced thrombus formation by 51.0+/-2.0. We propose a new orally active heparin, Db-LHD, in a solid dosage form to effectively prevent DVT and PE.

Investigation of direct toxic and teratogenic effects of anticoagulants on rat embryonic development using in vitro culture method and genotoxicity assay.

Heparin and low molecular weight heparins (LMWHs) are used to reduce the incidence of venous thromboembolism in pregnancy. Although, these agents have been shown to be safe when used during pregnancy, the studies about direct toxic and teratogenic effects of these drugs on embryonic development are limited. In this study, the effects of heparin and LMWHs on rat embryonic development were investigated by using in vitro embryo culture and micronucleus (MN) assay methods. Rat embryos were cultured in vitro in the presence of different concentrations of heparin (5-40 IU/ml), dalteparin (2.5-20 IU/ml), enoxaparin (25-100 microg/ml) and nadroparin (1-4 IU/ml). Effects of anticoagulants on embryonic developmental parameters were compared and embryos were evaluated for the presence of any malformations. After culturing the embryos, classic MN assay was performed. Anticoagulants significantly decreased all growth and developmental parameters dose-dependently. Dalteparin and enoxaparin were found to cause more developmental toxicity than heparin and nadroparin. Along with haematoma in general, heparin and nadroparin caused maxillary deformity, situs inversus and oedema most frequently, while neural tube defects were observed with dalteparin and enoxaparin. All agents also significantly induced MN formation in rat embryonic blood cells. These results indicate the possible genotoxic effects of anticoagulant agents on the developing rat embryo when applied directly.

Angiographic and clinical outcomes in patients receiving low-molecular-weight heparin versus unfractionated heparin in ST-elevation myocardial infarction treated with fibrinolytics in the CLARITY-TIMI 28 Trial.

BACKGROUND: Low-molecular-weight heparin (LMWH) offers pharmacological and practical advantages over unfractionated heparin (UFH). Whether these advantages translate into greater infarct-related artery patency and fewer adverse clinical events in patients with ST-elevation myocardial infarction (STEMI) receiving fibrinolytic therapy remains under study. METHODS AND RESULTS: We compared angiographic and clinical outcomes in patients treated with LMWH (n=1429) versus UFH (n=1431) in CLARITY-TIMI 28, a randomized trial of clopidogrel versus placebo in STEMI patients aged 18 to 75 years undergoing fibrinolysis. After comprehensive adjustment for baseline characteristics, therapeutic interventions, and a propensity score, treatment with LMWH was associated with a significantly lower rate of a closed infarct-related artery or death or myocardial infarction before angiography (13.5% versus 22.5%, adjusted OR 0.76, P=0.027). Treatment with LMWH was also associated with a significantly lower rate of cardiovascular death or recurrent myocardial infarction through 30 days (6.9% versus 11.5%, adjusted OR 0.68, P=0.030). The lower event rates were observed in patients allocated to clopidogrel and in those who underwent percutaneous coronary intervention. Rates of TIMI major bleeding through 30 days (1.6% versus 2.2%, P=0.27) and intracranial hemorrhage (0.6% versus 0.8%, P=0.37) were similar in the LMWH and UFH groups. Patients who received both clopidogrel and LMWH, in addition to a standard fibrinolytic and aspirin, had a particularly high rate of infarct-related artery patency (90.9%) and particularly low rates of cardiovascular death (3.2%), recurrent myocardial infarction (3.0%), and major bleeding (1.8%). CONCLUSIONS: In patients with STEMI receiving fibrinolytic therapy, use of LMWH with other standard therapies, including clopidogrel and aspirin, is associated with improved angiographic outcomes and lower rates of major adverse cardiovascular events.

Prevention of central venous line-related thrombosis by continuous infusion of low-dose unfractionated heparin, in patients with haemato-oncological disease. A randomized controlled trial.

We have conducted a prospective randomized controlled trial to evaluate the role of low-dose unfractionated heparin prophylaxis in preventing central venous line-related thrombosis in patients with haemato-oncological disease. Patients were randomly assigned to receive either prophylactic intravenous unfractionated heparin (continuous infusion of 100 IU/kg/daily) or 50 ml/daily of normal saline solution as a continuous infusion. CVLs were externalized, non tunneled, double lumen catheters. All CVLs were placed percutaneously by the same physician in the subclavian vein. Upper limb veins were systematically examined by ultrasonography just before, or <24 hours after, catheter removal, and in case of clinical signs of thrombosis. One hundred and twenty-eight CVLs were inserted. Catheter-related thrombosis occurred in 1.5% of the catheters inserted in patients of the heparin group, and in 12.6% in the control group (p = 0.03). No other risk factors were found for the development of catheter-related thrombosis. Two and three patients experienced severe bleeding in the heparin group, and in the control group, respectively (p = 0.18). There were no other side-effects clearly ascribable to the use of unfractionated heparin. This is the first prospective, randomized study, which shows that low-dose of unfractionated heparin is safe and effective to prevent catheter-related thrombosis in patients with haemato-oncological disease.

Efficacy and safety of bemiparin compared with enoxaparin in the prevention of venous thromboembolism after total knee arthroplasty: a randomized, double-blind clinical trial.

In this randomized, multicenter, controlled, double-blind, sequential trial, 381 patients undergoing primary total knee replacement were randomly assigned to receive subcutaneous injections of either 3500 IU anti-factor Xa of bemiparin sodium, first dose 6 h after surgery, or 40 mg of enoxaparin, first dose 12 h before surgery, followed by daily doses for 10 +/- 2 days, for the prophylaxis of venous thromboembolism. The primary efficacy endpoint was venous thromboembolism up to postoperative day 10 +/- 2, defined as deep vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep vein thrombosis and/or documented symptomatic pulmonary embolism. The primary safety endpoint was major bleeding. Eighty-seven percent of all randomized patients (333 of 381 patients) were evaluable for efficacy. The incidence of venous thromboembolism was 32.1% (53 of 165 patients) in the bemiparin group and 36.9% (62 of 168 patients) in the enoxaparin group. The absolute risk difference was 4.8% in favor of bemiparin [95% confidence interval (CI), -15.1% to 5.6%; non-inferiority P-value: 0.02; superiority P-value: 0.36]. The incidence of proximal deep vein thrombosis was 1.8% (three of 165 patients) in the bemiparin group and 4.2% (seven of 168 patients) in the enoxaparin group. Major bleeding occurred in six patients (three in each group). There were no deaths during the study. This trial shows that bemiparin started postoperatively is as effective and safe as enoxaparin started preoperatively in the prevention of venous thromboembolism in patients undergoing total knee replacement.

Endothelial damage after treatment with low-molecular weight heparins--a morphological study.

OBJECTIVE: Recent studies failed to show long-term benefit with low-molecular weight heparins (LMWH) in unstable coronary heart disease. A previous study of vascular effects of the cytostatic agent 5-fluorouracil (5-FU) showed that dalteparin prevented thrombosis induced by 5-FU but endothelial damage was not ameliorated and was present also in animals treated with dalteparin only. This study investigates the influence of LMWH currently in clinical use on arterial endothelium in vivo. DESIGN: Eighty rabbits in four groups were treated with dalteparin, enoxaparin, tinzaparin and saline, respectively. Arterial endothelium was examined after 3, 14, 30 and 60 days with scanning electron microscopy. RESULTS: All three groups treated with LMWH showed moderate damage to the endothelium, with contracted vessel wall and endothelial cells, cell membrane damage, denudation of subendothelium and adhering platelets. Contrarily, the control group exhibited a normal endothelium. CONCLUSION: Morphologic examination of arterial endothelium shows that all investigated LMWH exert a moderate toxic effect on endothelial cells. The clinical impact of these observations, e.g. concerning effect of long-term LMWH treatment, needs to be further elucidated.

Outpatient management of DVT using low molecular weight heparin and a hospital outreach service.

In recent years there have been several studies comparing the efficacy and safety of low molecular weight (LMW) and unfractionated heparin for the treatment of deep venous thrombosis (DVT), showing them in the clinical trial setting to be equal in these regards. LMWH has the advantage of once daily subcutaneous injection and daily monitoring of levels is not usually required. This has led many centres to develop outpatient treatment strategies for these patients but evidence for the safety of this approach is scarce. In 1997 we developed a hospital outreach service for the treatment of patients with DVT and, in a retrospective study, have compared the outcome in 172 patients treated at home with 172 age, sex and thrombotic risk factor matched inpatients treated at our institution with unfractionated heparin. Five patients in the home treatment group suffered a haemorrhagic event, compared with six patients in the hospital group. One patient in the home treatment group had a recurrent DVT within the first 3 months of treatment; in the hospital-treated group, six patients had recurrent DVTs and nine developed pulmonary emboli. At 3 months, there were three deaths in the home treatment group, compared with five deaths in the hospital group. There was no difference in re-admission rate at 3 months: 23 in the home treatment group, 24 in the hospital-treated group. Average length of hospital stay for the home-treatment group was 2.1 days and 12 days for the hospital group. Warfarin control was found to be significantly better in those patients treated at home, and only 18% of patients treated in hospital received heparin according to hospital guidelines. In conclusion, outpatient management of patients with DVT using LMWH is as safe as hospitalization and continuous infusion of unfractionated heparin. The complication rate was lower in the home treatment group and, in particular, the incidence of recurrent thrombosis was significantly less in the home treatment group. In addition, warfarin control was better when managed by specialist nurses. Patients expressed a preference for home treatment.

Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): in vitro evaluation of efficacy and toxicity.

Patients undergoing anticoagulation with heparin or low molecular weight heparin (LMWH) require a superior antidote that possesses more selective biological actions and a better safety profile than protamine. We had previously developed 2 low molecular weight protamine (LMWP) fractions (TDSP4 and TDSP5) from thermolysin-digested protamine as potential nontoxic, heparin-neutralizing agents. In this, the second article in this series, studies focused on in vitro evaluation of heparin/LMWH-neutralizing efficacy and putative toxicity. These LMWP fractions, particularly TDSP5, were effective and fully capable of neutralizing a broad spectrum of heparin-induced anticoagulant activities (ie, aPTT, anti-Xa, and anti-IIa activities). Additionally, these LMWP fractions could neutralize the activities of commercial LMWH. As assessed by the anti-Xa assay, TDSP5 was as effective as, although less potent than, protamine in reversing the activity of Mono-Embolex (molecular weight 5000-7000) and 2 other different sizes (molecular weight of 3000 and 5000 d) of LMWH preparations. Furthermore, compared with protamine, TDSP5 exhibited a much-reduced toxicity and thus an improved safety profile, as reflected by its reduced ability to activate the complement system and cross-react with the antiprotamine antibodies, which are 2 primary indices of protamine toxicity.

The outcome of ambulatory DVT management using a multidisciplinary approach.

Low molecular weight heparins (LMWHs) have been demonstrated to be at least as safe and effective as unfractionated heparin (UFH) in the initial management of deep vein thrombosis (DVT). However, the effectiveness of using LMWH in the ambulatory management of DVT in a 'real-life' setting has yet to be evaluated. This multicentre retrospective study involving 697 patients considers the outcome data of patients under- going ambulatory DVT treatment with tinzaparin (Innohep(R), Leo Pharmaceuticals, Risborough, Buckinghamshire, UK). During the 6 months following presentation, 17 (2.5%) patients had confirmed thromboembolic complications, of which 14 occurred subsequent to the initial LMWH treatment phase ('late'). There were no deaths in this group. Bleeding complications were reported in 23 (3.4%) patients, with 13 of these being classified as 'late'. Of these, two events were considered major resulting in hospitalization and death. Hospitalization for all causes was 6.8% (45 patients) with 32 patients being admitted for thromboembolic or bleeding complications. Overall mortality was 6.7%. These results compare favourably with published clinical trial data. This study demonstrates that ambulatory treatment of proven DVT with LMWH is both safe and effective.

Clinical experiences with low-molecular weight heparins in pediatric patients.

The courses of 79 children (2 weeks to 19 years old) treated with two different low-molecular weight heparins (LMWHs)--nadroparin (n=66) and enoxaparin (n=13)--were retrospectively analysed. In 62 patients, LMWHs were given for short-term prophylaxis (1-2 weeks) during immobilization after surgery or trauma. Thirteen children with thromboembolic events received long-term prophylaxis with LMWHs for 2-18 months--six after thrombolytic therapy and seven after therapy with unfractionated heparin (UFH). Because of thromboembolic events, four patients were initially treated with LMWHs. In all patients with short-term prophylaxis, no thrombosis occurred. After thrombolytic therapy, three children had no reocclusion, two had no thrombus apposition and one had complete recanalization. In the seven patients treated with LMWHs after UFH, four had no reocclusion, two had recanalization and one had reocclusion. In all patients receiving LMWHs for initial treatment of thrombosis, no thrombus apposition, but also no recanalization, occurred. For short-term prophylaxis, nadroparin was used independent of the body weight and without determination of anti-factor Xa (anti-FXa) activity. Long-term prophylaxis was given mainly as doses of 45-100 anti-FXa U/kg resulting in anti-FXa activities between 0.2 and 0.4 U/ml. For treatment of thrombosis, doses of 200-300 anti-FXa U/kg corresponded to 0.5-1.0 anti-FXa U/ml. Side effects--slight gastrointestinal bleeding and temporary reversible hair loss--were seen in two patients. In conclusion, LMWHs proved to be efficacious and safe especially in prophylaxis of thromboembolic events in children.