OBJECTIVE

The use of unfractionated heparin (UFH) in children is problematic. In adults, subcutaneous low-molecular-weight heparin (LMWH) is as effective as UFH in the treatment of thrombosis. Because pediatric data are limited, the authors studied the use of enoxaparin in children.

METHODS

Nineteen children (ages 18 days to 19 years; median age, 40 months) with indications for thrombosis treatment or prophylaxis were studied. Six patients (median age, 33 months), treated on a protocol that included pharmacokinetic studies, initially received enoxaparin 1 mg/kg subcutaneously every 12 hours; doses then were adjusted until target plasma levels of 0.5 to 1.2 anti-Xa U/mL were achieved. The records of 13 additional patients treated with enoxaparin off study were reviewed.

RESULTS

In the first six patients, enoxaparin pharmacokinetics was found to be similar to that in adults; once targeted levels were achieved, these remained stable. Among all 19 subjects, 14 had treatment of active thrombosis and 5 underwent thrombosis prophylaxis. For treatment of thrombosis, enoxaparin 1 mg/kg initially was administered subcutaneously every 12 hours. Target anti-Xa levels were achieved with 0.55 to 1.5 mg/kg every 12 hours (mean, 0.98 mg/kg; median, 1.0 mg/kg) in 1 to 7 days (median, 1 day). All patients in the treatment group had clinical improvement within 2 to 5 days, and 12 had follow-up radiological studies that confirmed this. For prophylaxis, enoxaparin was given at 1 mg/kg subcutaneously every 24 hours. No new thrombi were clinically evident in this group. There was no major bleeding with enoxaparin; one patient had transient mild mucosal oozing.

CONCLUSIONS

In this limited population, enoxaparin seems to be a safe, effective, and convenient alternative to UFH in children and adolescents. The adult therapeutic target range of 0.5 to 1.2 anti-Xa U/mL is readily achievable with a starting dose of 1 mg/kg every 12 hours in most children. Initial close monitoring with plasma anti-Xa activity should be done and doses adjusted to achieve target range, particularly in neonates. In the population of this study, enoxaparin seems as effective as UFH in the period immediately thrombotic episode. These results should be confirmed in the ongoing randomized trial comparing LMWH with UFH in children.

Low molecular weight heparins (LMWHs) are as efficient as unfractionated heparin (UFH) for prevention and treatment of thromboembolism. There is no evidence that monitoring the dose improves the clinical efficacy. In contrast, any overdosage increases the risk of hemorrhage. Because renal function plays a significant role in the elimination of LMWH, curative treatment should be monitored with an anti-factor Xa assay in patients presenting renal insufficiency, in the elderly, and in patients presenting an increased hemorrhagic risk. It is advisable to sample the patient at peak activity (3 to 5 hours after the subcutaneous [sc] administration) and to target the mean anti-factor Xa activity that was found efficient and safe in the clinical trial. This target is different for each LMWH and each dose regimen.

The efficacy and safety of low molecular weight heparin (LMWH), unfractionated heparin (UFH) and warfarin for prophylaxis of thrombo-embolism in orthopaedic surgery were compared using meta-analysis techniques. Twenty-two studies were included, 2 of which compared LMWH to warfarin. The mean probabilities to develop deep-vein thrombosis (DVT), pulmonary embolism and major and minor bleeding using UFH were: 0.21 (95% confidence interval, CI: 0.18-0.24); 0.01 (95% CI: 0.01-0.02); 0.05 (95% CI: 0.03-0.07), and 0.19 (95% CI: 0.17-0.22), respectively. The relative risk (RR) of DVT for LMWH vs. UFH was 0.76 (95% CI: 0.60-0.91), p < 0.05 and for LMWH vs. warfarin 0.78 (95% CI: 0.69-0.87), p < 0.05. The RR of minor bleeding for LMWH vs. UFH was 0.76 (95% CI: 0.64-0.92), p < 0.05. The RR of minor bleeding for LMWH vs. warfarin was 3.28 (95% CI: 2.21-4.70), p < 0.05.

CONCLUSIONS

in orthopaedic surgery, LMWH is significantly superior to both UFH and warfarin in the prevention of DVT and results in significantly less minor bleeding complications when compared to UFH, but significantly more minor bleeding when compared to warfarin.

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.

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.

BACKGROUND

To determine the efficacy and safety of heparin (unfractionated heparin (UFH) or low-molecular-weight-heparin (LMWH)) and fondaparinux in improving the survival of patients with cancer.

METHODS

We conducted in January 2007 a comprehensive search for relevant randomized clinical trials (RCTs). We used a standardized form to extract in duplicate data on methodological quality, participants, interventions and outcomes of interest including all cause mortality, thromboembolic events, and bleeding events. We assessed the methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology

RESULTS

Of 3986 identified citations, we included 5 RCTs, none of which evaluated fondaparinux. The quality of evidence was moderate for survival, low for major and minor bleeding, and very low for DVT. Heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio (HR) = 0.77; 95%CI = 0.65-0.91). In subgroup analyses, patients with limited small cell lung cancer experienced a clear survival benefit (HR = 0.56; 95%CI = 0.38-0.83). The survival benefit was not statistically significant for either patients with extensive small cell lung cancer (HR = 0.80; 95%CI = 0.60-1.06) or patients with advanced cancer (HR = 0.84; 95%CI = 0.68-1.03). The increased risk of bleeding with heparin was not statistically significant (relative risk (RR) = 1.78; 95%CI = 0.73-4.38).

CONCLUSIONS

This review suggests a survival benefit of heparin in cancer patients in general, and in patients with limited small cell lung cancer in particular.

OBJECTIVE

This study was designed to assess whether use of enoxaparin during percutaneous coronary intervention (PCI) increased bleeding compared with unfractionated heparin, in addition to background therapy with eptifibatide.

BACKGROUND

Data supporting the benefits of enoxaparin and the glycoprotein IIb/IIIa inhibitor eptifibatide evolved in parallel. Information on combining these two classes of medications is limited.

METHODS

A total of 261 patients undergoing elective or urgent PCI were randomized to either eptifibatide plus enoxaparin or eptifibatide plus unfractionated heparin.

RESULTS

The primary end point of the study, the bleeding index (change in hemoglobin corrected for blood transfusions), was 0.8 in the patients randomized to enoxaparin and 1.1 in patients randomized to unfractionated heparin (p = 0.15). The rate of vascular access site complications was 9.3% in the enoxaparin arm versus 9.8% in the unfractionated heparin arm (p = NS). The rate of bleeding complications was not significantly different between the two arms of the study, including in those patients who received vascular closure devices. The rate of angiographic complications was 6.3% in the enoxaparin group and 6.2% in the unfractionated heparin group (p = NS). Similarly, there were no significant differences in the composite of death, myocardial infarction, or urgent target vessel revascularization at 48 h or 30 days.

CONCLUSIONS

Compared with unfractionated heparin plus eptifibatide, the combination of enoxaparin plus eptifibatide is not associated with an excess of bleeding or vascular complications, including in those receiving closure devices. Despite no monitoring of anticoagulation activity with enoxaparin, there was no apparent increase in angiographic or clinical complications.

OBJECTIVE

To compare the efficacy and safety of low molecular weight heparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction.

RESULTS

Three-hundred patients receiving fibrinolytic therapy following acute myocardial infarction were randomly assigned to low molecular weight heparin as enoxaparin (40 mg intravenous bolus, then 40 mg subcutaneously every 8 h, n=149) or unfractionated heparin (5000 U intravenous bolus, then 30 000 U. 24 h(-1), adjusted to an activated partial thromboplastin time 2-2.5x normal, n=151) for 4 days in conjunction with routine therapy. Clinical and therapeutic variables were analysed, in addition to use of enoxaparin or unfractionated heparin, to determine independent predictors of the 90-day composite triple end-point (death, non-fatal reinfarction, or readmission with unstable angina). The triple end-point occurred more frequently in patients receiving unfractionated heparin rather than enoxaparin (36% vs. 26%; P=0.04). Logistic regression modelling of baseline and clinical variables identified the only independent risk factors for recurrent events as left ventricular failure, hypertension, and use of unfractionated heparin rather than enoxaparin. There was no difference in major haemorrhage between those receiving enoxaparin (3%) and unfractionated heparin (4%).

CONCLUSIONS

Use of enoxaparin compared with unfractionated heparin in patients receiving fibrinolytic therapy for acute myocardial infarction was associated with fewer recurrent cardiac events at 90 days. This benefit was independent of other important clinical and therapeutic factors.

Given the increased number of patients hospitalized for acute medical illnesses and the associated risk of venous thromboembolism (VTE), the use of prophylaxis has become a public health matter. Thromboprophylaxis is not widely practiced in acutely ill medical patients, due in part to the heterogeneity of this group and the perceived difficulty in assessing those who would most benefit from treatment. Nevertheless, the results of recent well-conducted clinical trials support the evidence-based recommendations for more widespread systematic use of low-dose low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in this population. Three large well-controlled studies (MEDENOX, PREVENT, and ARTEMIS) in acutely ill medical patients confirm previous findings that different at-risk patient populations show a consistent 50% reduction in VTE events with LMWH and fondaparinux. A meta-analysis in nearly 5000 patients in internal medicine comparing UFH and LMWH revealed a trend for reduction of deep vein thrombosis and pulmonary embolism with LMWH. Based on duration of use in clinical trials in acutely ill medical patients, prophylactic treatment with UFH and LMWH is recommended for 2 weeks.

Human umbilical vein endothelial cells (HUVEC) were used as an experimental host model to investigate the mechanism(s) of streptococcal adhesion in infective endocarditis. Adhesion activity of Streptococcus gordonii was maximal during the logarithmic phase of growth and was greatly reduced or eliminated by pretreatment of bacteria with heat, formaldehyde, or trypsin. At saturating numbers of streptococci, an average of 81 bacteria were bound per HUVEC. Streptococcal adhesion was inhibited by low-molecular-weight dextran and heparin but not by sucrose, fibronectin, or laminin. Adhesion was also prevented by pretreatment of HUVEC with proteins dissociated from the surface of S. gordonii with 10 mM EDTA or isolated from spent culture medium. Western blot (immunoblot) assays detected a single adhesion protein of 153 kDa (AP153) on HUVEC after incubation with unfractionated extracts of streptococci. The adhesin exhibited glucosyltransferase (GTF) activity when incubated with sucrose and Triton X-100 after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The AP153 was purified by affinity chromatography on dextran beads and show to have binding activity for HUVEC, GTF activity, an amino acid composition similar to that reported for GTF of S. gordonii, and the ability to inhibit S. gordonii adhesion. Incubation of the streptococci with antibodies to the adhesin inhibited bacterial attachment to HUVEC monolayers. These results indicate that surface-localized GTF mediates adhesion of S. gordonii to HUVEC in vitro and may serve as a mechanism for colonization of the endocardium in infective endocarditis.

BACKGROUND

Controlled clinical trials have demonstrated that outpatient administration of low-molecular-weight heparin to patients with acute deep vein thrombosis (DVT) provides safety and efficacy equivalent to that of traditional inpatient therapy with unfractionated heparin. Whether favorable results reported in controlled clinical trials are achievable in clinical practice is an important consideration.

METHODS

Appropriate patients with objectively diagnosed DVT were treated as outpatients with low-molecular-weight heparin and warfarin sodium according to an approved guideline. The primary end point for analysis consisted of objectively diagnosed symptomatic recurrent thromboembolism or major bleeding within a 90-day evaluation period. The incremental cost incurred by the organization while using the outpatient DVT treatment guideline was determined. Incremental cost savings of the outpatient DVT treatment program were determined based on the cost that would have accrued had the patient been admitted to the hospital for treatment with unfractionated heparin.

RESULTS

We enrolled 391 patients (91.4%) in the outpatient DVT treatment program. Of these, 373 (95.4%) completed 90 days of therapy without reaching the primary end point. The percentage of patients reaching the primary outcome measure (4.6%) fell within the range of patients enrolled in controlled clinical trials (3.5%-9.4%). During the 2-year program evaluation, total cost savings of $1,108,587 were realized.

CONCLUSIONS

Outpatient treatment of acute DVT can be managed safely and effectively in clinical practice. The potential savings associated with outpatient DVT treatment are substantial. Arch Intern Med. 2000;160:2926-2932

BACKGROUND

Enoxaparin was shown to be superior to unfractionated heparin in the patients with non-ST-segment elevation acute coronary syndromes (ACS) in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events study and the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. However, enoxaparin has had limited acceptance in clinical practice, in part because of the contemporary management of these patients, which includes glycoprotein IIb/IIIa inhibition and the use of early invasive management strategies.

METHODS

The Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is an 8000-patient, prospective, randomized, open-label, multicenter investigation of enoxaparin compared with unfractionated heparin in patients at high risk with non-ST-segment elevation ACS treated with an early invasive strategy. The primary efficacy end point is death or nonfatal myocardial infarction 30 days after enrollment.

CONCLUSIONS

The SYNERGY trial is the largest study currently planned for the acute therapy of patients with non-ST-segment elevation ACS and the first large trial since the publication of the revised American College of Cardiology/American Heart Association guidelines for the management of these patients. In addition to evaluating the potential superiority of enoxaparin over unfractionated heparin, this investigation will provide important observations of current treatment strategies in patients with ACS.

Ovarian cancer cells appear to be capable of both thrombin formation and induction of fibrin degradation which may be essential prerequisites for the development of deep vein thrombosis (DVT) as well as the spread of malignancy. To study further this coagulation-cancer interaction in 60 patients with untreated ovarian cancer of FIGO stage I-IV the incidence of DVT was recorded pre-operatively, post-operatively on day 1, 3, 5, 7, 10, before each of six cycles of Cisplatinum/ Epirubicin/Cyclophosphamide chemotherapy, during follow-up and in the post-operative period of second look surgery. In addition, blood coagulation tests results were determined prospectively. Two patients were excluded from these calculations due to previous DVT 5 to 6 weeks before the diagnosis of ovarian cancer but all patients were eligible for surgery and randomized to receive either daily low molecular weight heparin (LMWH) (n = 28) or unfractionated heparin (UFH) (n = 32) for perioperative thrombosis prophylaxis until the 7th post-operative day. According to the FIGO stage, patients were equally distributed in the 2 heparin treatment groups. The predictive value of pre-operative coagulation test results, clinical parameters, and type of heparin used were tested in univariate and multivariate analysis for development of post-operative DVT and overall patients survival. Impedance plethysmography for DVT screening was used. The presence of DVT was then confirmed by phlebography. Only D-dimer and fibrinogen levels were correlated significantly with the FIGO stage while antithrombin, protein C, and plasminogen activator inhibitor activity were not. The incidence of DVT was 6.7% (4/60) up to the 7th and 8.3% (5/60) between the 8th and 29th post-operative day. DVT occurred in 10.6% (5/47) during chemotherapy. Pre-operative coagulation test results, the type of heparin used, and clinical parameters were not significant risk factors for post-operative DVT development in univariate analysis. The D-dimer and fibrinogen levels were significant risk factors for reduced overall survival in univariate analysis but only the FIGO stage was an independent predictor (in multivariate analysis). After a median follow up of 26.5 months (min. 8 months, max. 41 months), 21.4% of LMWH treated and 37.5% of UFH-treated patients died of cancer (p = 0.26). Pre-operative test results were neither predictive for DVT nor the outcome of cancer but patients showed an improved though not statistically significant overall survival after LMWH treatment.

Lysophosphatidylcholine (LysoPC) is an important intermediate in degradation and biosynthesis of phosphatidylcholine (PC). Reduced plasma LysoPC levels observed in patients with advanced cancer indicate a deregulation of LysoPC metabolism in metastasis. Recent data showed strong antimetastatic effects of liposomes consisting of saturated PC in a murine pancreatic metastasis model. LysoPC, generated from saturated PC after accumulation of the liposomes in tumor tissue, might be contributing to these effects. Examining effects of high local concentrations of saturated LysoPC and investigating potential molecular mechanisms, fast removal of saturated LysoPC from medium by murine B16.F10 melanoma cells and radical shifts in tumor cell membrane fatty acid (FA) composition toward saturated FAs were observed in vitro. Scanning electron microscopy revealed remarkable morphologic surface changes of LysoPC-treated tumor cells, probably causing their impaired migratory ability on fibronectin. A LysoPC concentration exceeding a threshold of about 400 μmol/L, slightly above physiologic levels, strongly reduced VLA-4-mediated binding of B16.F10 cells to VCAM-1 as well as P-selectin-dependent interaction with activated platelets, although expression levels were not altered. These findings were reflected in a syngenic intravenous lung invasion model using repeatedly ex vivo LysoPC-treated (450 μmol/L) B16.F10 cells, resulting in significantly reduced lung metastasis-like lesions (-48.3%, P = 0.006). Prior application of 50 IU unfractionated heparin further reduced lung invasion (-81.6%, P = 0.043). Our work shows for the first time that saturated LysoPC in high concentrations reduces melanoma cell adhesion in vitro and hematogeneous dissemination in vivo by direct ex vivo tumor cell targeting.

OBJECTIVE

Thromboprophylaxis with low-molecular-weight heparin (LMWH) may be more effective than unfractionated heparin but also more likely to bioaccumulate and potentially cause bleeding in patients with renal insufficiency. The objectives of this study were to assess, among medical-surgical patients in the intensive care unit receiving dalteparin 5,000 IU daily for thromboprophylaxis, (1) the relationship between renal dysfunction and LMWH bioaccumulation as measured by trough anti-Xa levels, (2) the relationship between renal dysfunction and risk of bleeding as measured by a surrogate marker (peak anti-Xa levels), and (3) the relationship between anti-Xa levels, bleeding events, and thrombotic events.

METHODS

In this prospective single-center cohort study, we enrolled patients 18 years or older, expected to stay 72 hours or longer, and with a creatinine clearance 30 mL/min or higher at intensive care unit admission. We administered 5,000 IU dalteparin subcutaneously each day. The main phase 1 objective was to detect bioaccumulation of dalteparin by measuring trough anti-Xa levels (22-23 hours post dalteparin). The main phase 2 objective was to examine the relationship between renal dysfunction and peak anti-Xa levels (4 hours post dalteparin). We recorded creatinine clearance daily and bleeding and thrombotic events, blinded to anti-Xa levels.

RESULTS

We enrolled 19 patients aged 62.7 (13.2) years with an APACHE II score of 23.5 (9.4). We measured trough anti-Xa levels on 185 occasions in 19 patients; we measured peak anti-Xa levels on 113 occasions in 11 patients. We identified no bioaccumulation of LMWH in this study, as detected by trough anti-Xa levels. Most peak anti-Xa levels were in the conventional prophylactic range.

CONCLUSIONS

When administered in prophylactic doses to critically ill patients with a wide range of calculated creatinine clearances, we found no evidence of bioaccumulation of dalteparin. If dalteparin does not bioaccumulate, it may be an attractive alternative agent for thromboprophylaxis.

BACKGROUND

Recent advances in the understanding of blood coagulation processes favor an inflammatory basis for thrombotic events. In this study, thrombotic risk after total knee arthroplasty (TKA) was assessed and compared between patients with rheumatoid arthritis (RA) and those with osteoarthritis (OA).

METHODS

Subjects comprised 199 patients (238 knees) with RA and 156 patients (169 knees) with OA. Serum D-dimer levels were measured before and after the operation. Lowdose unfractionated heparin was given for 7 days when patients had a history of previous venous thromboembolism or had a D-dimer level or>>or=10 microg/ml of D-dimer on postoperative day 1. Doppler ultrasonography (DUS) was routinely performed preoperatively and on postoperative day (POD) 7 for diagnosing a deep venous thrombosis (DVT).

RESULTS

D-dimer levels on PODs 0, 1, and 7 were, respectively, 4.6, 37.2, and 11.2 microg/ml for RA and 1.8, 42.3, and 13.6 microg/ml for OA. The incidence of DUS-confirmed DVT was 20.6% in the RA group and 43.2% in the OA group, indicating a much higher incidence of postoperative DVT in OA patients (P < 0.001). Interestingly, when patients taking nonsteroidal antiinflammatory drugs (NSAIDs) or those >65 years of age were excluded, the incidence of DVT was comparable in the RA and OA groups. Symptomatic pulmonary embolism and DVT occurred in two and one OA patients and in one and two RA patients, respectively, with one postdischarge DVT included in each group.

CONCLUSIONS

The present study revealed that the incidence of DVT following TKA was significantly lower in RA patients than in those with OA. However, when the patients were matched for age and NSAID use, the incidence of DVT was equivalent in the two groups. These findings may allow us to reconsider a prophylactic regimen for venous thromboembolism in patients with RA.

Low molecular weight heparin (LMWH) fragments have recently been proposed as antithrombotic drugs. Several fractions and fragments have been studied in human healthy volunteers: Enoxaparin (Lovenox) from Pharmuka, Fraxiparin from Choay, Fragmin from Kabi, LHN1 from Novo laboratories. The pharmacokinetics of LMWH are clearly different from those of unfractionated heparin as demonstrated by a small group of studies. In our laboratory, we undertook one study with enoxaparin. After intravenous and sub-cutaneous injection the clearance half-life of the different LMW heparins is about 3 to 4 hours. It is significantly longer for LMW heparin than for unfractionated heparin. The half-life of anti-IIa activity is similar for LMW heparins and for unfractionated heparin. However, contrary to unfractionated heparin, there is, for Enoxaparin, a difference between the two activity half-life. The anti-IIa activity half-life is smaller than that of anti-Xa activity. After intravenous and sub-cutaneous injection of 30 to 40 mg of the different fragments and fractions the biodisponibility of LMWH S.C.(A.U.C.) I.V.(A.U.C.) was about 4 times higher when compared to unfractionated heparin injected at a dose of 29 mg. In a recent study with 12 volunteers, using S.C. administration of 20, 40, 60, and 80 mg of Enoxaparin, we were able to demonstrate a good linearity between the area under the curves and the injected doses. Standard heparin is mainly cleared by a cellular mechanism while LMWH is essentially cleared by a renal mechanism. Anti-Xa activities obtained by the chromogenic technique are higher than those obtained in human plasmas with a competitive binding assay and with labelled Enoxaparin in the dog and in the rat. The persistent anti-Xa activity may be mediated by some compounds released by Enoxaparin.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of unfractionated heparin and the low-molecular-weight (LMW) heparin PK 10169 after intravenous and subcutaneous injection were compared by crossover study in 8 healthy volunteers. The heparin concentrations in plasma were measured by a competitive binding assay, and anti-IIa and anti-Xa activities were also assayed. Unfractionated heparin was cleared after intravenous administration with a half-life of 35 min irrespective of assay method. However, the concentration of PK 10169 declined with the longer half-life of 60 min, and its anti-IIa and anti-Xa activities had half-lives of 40 and 275 min, respectively. Some of this anti-Xa activity may be mediated by a compound released by PK 10169 rather than by the LMW heparin itself. The bioavailability of PK 10169 was 3-fold greater than that of unfractionated heparin, due to more effective absorption after subcutaneous administration.

Human serum spreading factor (SF) is a blood glycoprotein that promotes attachment and spreading and influences growth, migration, and differentiation of a variety of animal cells in culture. SF purified from human plasma or serum by chromatographic methods reported previously (Barnes, D. W., and Silnutzer, J. (1983) J. Biol. Chem. 258, 12548-12552) does not bind to heparin-Sepharose under conditions of physiological ionic strength and pH. In a further examination of the heparin-binding properties of human serum SF, we found that exposure of purified SF to 8 M urea altered several properties of the protein, including heparin affinity, and these alterations remained after removal of the urea from SF solutions. Urea-treated SF bound to heparin under physiological conditions, and salt concentrations of 0.4 M or higher were required for elution of urea-treated SF from heparin-Sepharose at pH 7.0. The alteration of heparin-binding properties of SF also was observed upon exposure of the protein to heat or acid. Treatment of SF with urea, heat, or acid resulted additionally in greatly decreased cell spreading-promoting activity of the molecule. The decreased biological activity was associated with a reduced ability of the treated SF to bind to the cell culture substratum, a prerequisite for the attachment-promoting activity of the molecule. Experiments examining the heparin-binding properties of native SF in unfractionated human plasma indicated that the major portion of SF in blood did not bind to heparin under conditions of physiological ionic strength and pH.

OBJECTIVE

The development of venothromboembolisms (VTEs), including deep vein thrombosis (DVT) and pulmonary emboli (PE), is common in brain tumor patients. Their development can be catastrophic. Studies evaluating pre-operative clinical factors that predispose patients to the development of VTE are few and limited. An understanding may help risk stratify patients and guide subsequent therapy aimed at reducing the risk of DVTs/PEs.

METHODS

All adult patients who underwent surgery for an intracranial tumor at an academic tertiary care institution between 1998 and 2008 were retrospectively reviewed. Stepwise multivariate logistical regression analysis was used to identify pre-operative factors associated with the development of peri-operative (within 30 days of surgery) DVTs/PEs among patients who underwent surgery of their intracranial tumor.

RESULTS

Of the 4293 patients in this study, 126 (3%) patients developed DVT and/or PE in the peri-operative period. The pre-operative factors independently associated with the development of DVTs/PEs were: poorer Karnofsky performance scale (KPS) [odds ratio (OR), 1·040; 95% confidence interval (CI), 1·026-1·052; P<0·0001], high grade glioma (OR, 1·702; 95% CI, 1·176-2·465; P = 0·005), older age (OR, 1·033; 95% CI, 1·020-1·046; P<0·0001), hypertension (OR, 1·785; 95% CI, 1·180-2·699; P = 0·006), and motor deficit (OR, 1·854; 95% CI, 1·244-2·763; P = 0·002). Eighty six per cent of the patients with DVTs/PEs were treated with either unfractionated or low molecular weight heparin, and 4% of these patients developed intracranial hemorrhage.

CONCLUSIONS

The present study found that poorer functional status, older age, pre-operative motor deficit, high grade glioma, and hypertension each independently increased the risk of developing peri-operative DVTs/PEs. These findings may provide patients and physicians with prognostic information that may guide therapies aimed at minimizing the development of peri-operative DVTs/PEs.

BACKGROUND

Low-molecular-weight heparin (LMWH) has been suggested as providing safe, efficient, convenient and possibly more cost-effective anticoagulation for haemodialysis (HD) than unfractionated heparin, with fewer side-effects and possible benefits on uraemic dyslipidaemia.

METHODS

In this prospective, randomized, cross-over study we compared the safety, clinical efficacy and cost effectiveness of Clexane (enoxaparin sodium; Rhône-Poulenc Rorer) with unfractionated heparin in 36 chronic HD patients. They were randomly assigned to either Clexane (1 mg/kg body weight, equivalent to 100 IU) or standard heparin, and followed prospectively for 12 weeks (36 dialyses) before crossing over to the alternate therapy for a further 12 weeks. Heparin anticoagulation was monitored using activated coagulation times.

RESULTS

Dialysis with Clexane resulted in less frequent minor fibrin/clot formation in the dialyser and lines than with heparin (P<0.001), but was accompanied by increased frequency of minor haemorrhage between dialyses (P<0.001). Clexane dose reduction (to a mean of 0.69 mg/kg) eliminated excess minor haemorrhage without increasing clotting frequencies. Mean vascular compression times were similar in both groups. Over 24 weeks, no changes in standard serum lipid profiles were observed.

CONCLUSIONS

This study suggests that a single-dose protocol of Clexane is an effective and very convenient alternative to sodium heparin, but currently direct costs are about 16% more. We recommend an initial dose of 0.70 mg/kg.

1. The signal transduction mechanism of ginsenosides, the active ingredients of ginseng, was studied in Xenopus oocytes using two-electrode voltage-clamp technique. Ginseng total saponin (GTS), i.e., an unfractionated mixture of ginsenosides produced a large outward current at membrane potentials more positive than -20 mV when it was applied to the exterior of oocytes, but not when injected intracellularly. The effect of GTS was concentration-dependent (EC(50): 4.4 microg ml(-1)) and reversible. 2. Certain fractionated ginsenosides (Rb(1), Rb(2), Rc, Rf, Rg(2) and Ro) also produced an outward current in a concentration-dependent manner with the order of potency of Rf>Ro>Rb(1)=Rb(2>>Rg(2>>Rc. Other ginsenosides (Rd, Re and Rg(1)) had little or no effect. 3. The GTS effect was completely blocked by bath application of the Ca(2+)-activated Cl(-) channel blocker niflumic acid and by intracellular injection of the calcium chelator BAPTA or the IP(3) receptor antagonist heparin. Also, the effect was partially blocked by bath-applied U-73122, a phospholipase C (PLC) inhibitor and by intracellularly injected GTP gamma S, a non-hydrolyzable GTP analogue. Whereas, it was not altered by pertussin toxin (PTX) pretreatment. 4. These results indicate that: (1) interaction of ginsenosides with membrane component(s) at the extracellular side leads to Ca(2+)-activated Cl(-) channel opening in Xenopus oocyte membrane; and (2) this process involves PLC activation, the release of Ca(2+) from the IP(3)-sensitive intracellular store and PTX-insensitive G protein activation.

Aneurysmal subarachnoid hemorrhage (SAH) is associated with numerous "delayed neurological deficits" (DNDs) that have been attributed to multiple pathophysiological mechanisms, including ischemia, microthrombosis, free radical damage, inflammation, and vascular remodeling. To date, effective prophylactic therapy for SAH-induced DNDs has been elusive, due perhaps to the multiplicity of mechanisms involved that render typical, single-agent therapy seemingly futile. We hypothesized that heparin, which has multiple underappreciated salutary effects, might be useful as a multitargeted prophylactic agent against SAH-induced DNDs. We performed a comprehensive review of the literature to evaluate the potential utility of heparin in targeting the multiple pathophysiological mechanisms that have been identified as contributing to SAH-induced DNDs. Our literature review revealed that unfractionated heparin can potentially antagonize essentially all of the pathophysiological mechanisms known to be activated following SAH. Heparin binds >100 proteins, including plasma proteins, proteins released from platelets, cytokines, and chemokines. Also, heparin complexes with oxyhemoglobin, blocks the activity of free radicals including reactive oxygen species, antagonizes endothelin-mediated vasoconstriction, smooth muscle depolarization, and inflammatory, growth and fibrogenic responses. Our review suggests that the use of prophylactic heparin following SAH may warrant formal study.

OBJECTIVE

To investigate if pulmonary delivery of low molecular weight heparin (LMWH) formulated with tetradecyl-beta-maltoside (TDM) or dimethyl-beta-cyclodextrin (DMbetaCD) could be a feasible alternative to subcutaneous injections for the treatment of pulmonary embolism.

METHODS

The pulmonary absorption of two LMWHs and unfractionated heparin formulated with TDM or DMbetaCD was studied in cell culture and rodent model. The in vitro study was performed by measuring the transport of radiolabeled enoxaparin and mannitol across human bronchial epithelial cells (Calu-3) in the presence or absence of varying concentrations of TDM or DMbetaCD. The changes in transepithelial electrical resistance (TEER) and enoxaparin metabolic stability were also investigated using Calu-3 cells. In vivo absorption studies were performed by measuring plasma anti-factor Xa activity after pulmonary administration of enoxaparin, dalteparin, or unfractionated heparin to anesthetized rats.

RESULTS

In vitro experiments conducted in Calu-3 cells suggest that the addition of TDM or DMbetaCD to the apical chamber results in a significant increase in 3H-enoxaparin and 14C-mannitol permeability and a decrease in TEER across the Calu-3 cell monolayer. Enoxaparin incubated in Calu-3 cell extracts was stable for 8 h. In vivo studies indicate that both TDM and DMbetaCD enhance pulmonary absorption of LMWH. However, TDM was found to be more potent than DMbetaCD in both in vitro transport and in vivo absorption studies.

CONCLUSIONS

TDM and DMbetaCD enhance pulmonary absorption of LMWH both in vitro and in vivo, with TDM being more efficacious than DMbetaCD. Both agents increase drug transport by acting mainly on the membrane rather than interacting with the drug.

OBJECTIVE

We examined the lytic effects of anti-glycoprotein (GP) IIb/IIIa agents on platelet thrombi formed on the collagen surface under blood flow conditions.

BACKGROUND

Anti-GP IIb/IIIa agents may influence platelet thrombi already formed.

METHODS

Blood samples were anticoagulated either by the specific antithrombin Argatroban (100 microM) or by unfractionated heparin (0.1 U/ml). After platelet thrombi were formed on a collagen surface following 6-min perfusion of whole blood obtained from eight adult donors containing fluorescinated platelets at a wall shear rate of 1,500 s(-1), additional blood samples from the same donors either containing or not containing anti-GP IIb/IIIa agents (abciximab, eptifibatide, or tirofiban) were perfused on these thrombi. The three-dimensional structures of the platelet thrombi were continuously observed by laser confocal microscopy equipped with a piezo-electric motor control unit and recorded.

RESULTS

The platelet thrombi started to dissolve after perfusion of blood containing the anti-GP IIb/IIIa agents, whereas their growth resumed after subsequent perfusion of control blood. Only a single layer of platelets having heights of 3 +/- 1 microm, 3 +/- 2 microm, and 3 +/- 1 microm, respectively, could be seen after 6-min perfusion of blood containing abciximab, eptifibatide, and tirofiban, whereas the initial height of the platelet thrombi of 8 +/- 2 microm increased to 11 +/- 4 microm after subsequent perfusion of control blood (n = 8). The volume of the platelet thrombi, which was 3,352 +/- 1,045 microm(3) before starting the second perfusion, was reduced to 778 +/- 102 microm(3), 812 +/- 122 microm(3), and 856 +/- 144 microm(3) after 6-min perfusion of blood containing abciximab, eptifibatide, and tirofiban, respectively.

CONCLUSIONS

We have shown in this study that anti-GP IIb/IIIa agents possess the ability to dissolve platelet thrombi.