AVE5026: A New Hemisynthetic Ultra Low Molecular Weight Heparin with Enriched Anti-Xa Activity and Enhanced Antithrombotic Activity for Management of Cancer Associated Thrombosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4046-4046
Author(s):  
Debra Hoppensteadt ◽  
Walter Jeske ◽  
Jeanine M. Walenga ◽  
Jawed Fareed
Keyword(s):  
Molecular Weight ◽  
Animal Models ◽  
Tumor Growth ◽  
Bleeding Risk ◽  
Repeated Administration ◽  
Therapeutic Window ◽  
Bleeding Effect ◽  
Polydisperse Mixture ◽  
Antithrombotic Efficacy ◽  
Cancer Associated Thrombosis

Abstract AVE5026 is an ULMWH with a high anti-Xa activity associated with residual anti-IIa activity (ratio anti-Xa/IIa>30). This ratio may be favorable for use in cancer patients as it may have a higher therapeutic window. This agent is a polydisperse mixture of oligomeric heparin fragments (molecular weight 2000–3000 daltons) prepared by partial and controlled depolymerization of porcine mucosal heparin (UFH).. The anticoagulant profile of AVE5026 has been previously reported (Hoppensteadt, et al. Blood 2007). To validate the hypothesis that AVE5026 is an appropriate antithrombotic in cancer, studies were carried out to determine its antithrombotic, bleeding, tumor growth, angiogenesis and apoptosis effects in animal models. AVE5026 produced a dose-dependent antithrombotic response in the rat laser model of microvascular thrombosis (2.5 mg/kg IV, 9±1.7 laser shots; 5.0 mg/kg SC, 8±1.6 laser shots; control 3±0.8 laser shots). The relative bleeding effects of AVE5026 in a rat tail bleeding model were negligible in comparison to enoxaparin (E) and UFH (all 5 mg/kg IV; UFH >1000 sec; E 360±57 sec; AVE5026 209±29 sec; Control 215±32 seconds). Repeated administration of AVE5026 in dose ranges of 1–5 mg/kg od, SC for 14 days did not result in accumulation of the anti-Xa activity. Furthermore, in contrast to E, there was no enhancement of the hemorrhagic profile. Both E and AVE5026 inhibited tumor growth by regulating angiogenesis and apoptosis in a Lewis Lung carcinoma (14% vs. 22% decrease) rat model and in a Walker 256 carcinosarcoma model (21% vs. 30% decrease) Although comparable results to E were demonstrated in animal models of arterial thrombosis, the bleeding effect of AVE5026 were disproportionately lower. This superior safety-efficacy ratio may translate into improved antithrombotic efficacy with decreased bleeding risk, suggesting that AVE5026 may provide the optimal treatment strategy for the management of cancer associated thrombosis.

Effect of Heparin and Its Derivatives On the Progression of Tumor Growth in Mouse Lewis Lung Carcinoma Model.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2274-2274 ◽  
Author(s):  
Debra Hoppensteadt ◽  
Arslan Chaudhry ◽  
Angel Gray ◽  
Matthew Hejna ◽  
Jawed Fareed
Keyword(s):  
Molecular Weight ◽  
Tumor Growth ◽  
Low Molecular Weight Heparin ◽  
Ex Vivo ◽  
Saline Control ◽  
Spleen Weight ◽  
Low Molecular Weight ◽  
Significant Difference ◽  
Lewis Lung Carcinoma Model ◽  
Cancer Associated Thrombosis

Abstract Abstract 2274 Background: Unfractionated heparin and it derivatives are known to produce pleotropic effects including the anticoagulant, anti-inflammatory and antitumor actions. Preclinical evidence suggests that heparins have an effect on tumor progression independent of their anticoagulant activity. Heparin and low molecular weight heparin have also been shown to exhibit interactions with growth factors and other cellular receptors. Recently an ultra low molecular weight heparin namely, semuloparin has also been found to be effective in the management of cancer associated thrombosis (Save ONCO trial). This study was designed to investigate whether heparin and its derivatives are able to inhibit tumor growth in a Lewis Lung carcinoma model. Methods: Female C57BL/6 mice were obtained at 6–8 weeks of age and were implanted with 5×105 LN7 tumor cells by dorsal subcutaneous injection in the upper back. When tumors were initially palpable, at 7–10 days of growth, mice were treated with subcutaneous injections of heparin, a low molecular weight heparin (LMWH), namely enoxaparin, an ultra LMWH, semuloparin or saline, daily for two weeks at approximately 1 cm away from the tumor growth, in a dose range of 1.0 – 0.25 mg/kg. After the treatment period, animals were sacrificed and the spleens and tumors were removed and tumor weight, tumor volume, spleen weight and spleen size were measured. Blood samples were drawn through heart puncture for ex vivo analysis. VEGF levels were measured using a commercially available ELISA method. Results: At the 1.0 and 0.5 mg/kg dosages, both enoxaparin (p<0.01) and semuloparin (p<0.01) showed a decrease in tumor volume compared to the saline control animals. At the 1.0 mg/kg dosage although heparin was effective in reducing the tumor size, the mortality was higher in this group due to bleeding. At 0.5 mg/kg heparin was not different from the saline control in terms of reducing tumor growth. In addition, at a dosage of 0.25 mg/kg, only semuloparin showed a significant difference in reducing the tumor size in comparison to saline control (p<0.01). Similar results were observed for the tumor weight. There were no significant differences noted in spleen weight or spleen size among these agents. The mortality rates in the mice treated with enoxaparin and semuloparin were relatively lower (<10%) and were comparable between the two groups. Ex vivo analysis of blood showed a significant difference in the VEGF levels in the semuloparin group in comparison to enoxaparin and heparin. Conclusions: These studies suggest that heparin and its derivatives are capable of inhibiting tumor growth in a dose dependent manner. Enoxaparin and semuloparin are more effective at reducing tumor growth compared to heparin. In addition, both the enoxaparin and semuloparin were safer than heparin at the 1.0 and 0.5 mg dosages as bleeding was observed in the heparin treated animals. Semuloparin downregulated the VEGF levels in comparison to the other groups suggesting that this mechanism potentially plays a role in the control of the tumor growth. Reported clinical studies have shown that semuloparin is safer and effective for the prevention of venous thromboembolism in cancer patients and compares favorably to enoxaparin in terms of antithrombotic effect and safety profile. Therefore, semuloparin may be a better alternate for the management of cancer associated thrombosis. Disclosures: No relevant conflicts of interest to declare.

HES 200/0.5 Is not HES 200/0.5

1995 ◽  
Vol 74 (06) ◽  
pp. 1452-1456 ◽  
Author(s):  
Johannes Treib ◽  
Anton Haass ◽  
Gerhard Pindur ◽  
Ulrich T Seyfert ◽  
Wolfgang Treib ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Hydroxyethyl Starch ◽  
Clinical Relevance ◽  
Dilution Effect ◽  
Repeated Administration ◽  
Plasma Viscosity ◽  
Degree Of Substitution ◽  
Pronounced Increase ◽  
Large Molecules ◽  
Mean Molecular Weight

SummaryThe plasma clearance of hydroxyethyl starch (HES) depends on the initial molecular weight and the degree of substitution. So far, little attention has been paid to the clinical relevance of the C2/C6 substitution ratio of hydroxyethyl starch.10 patients with cerebrovascular circulatory disturbance received hemodilution therapy for 10 days, consisting of 10% HES 200/0.5 (mean molecular weight 200 kD, degree of substitution 0.5) with a C2/C6 ratio of 13.4. A second group of 10 patients received a starch solution with identical initial molecular weight and degree of substitution but with a C2/C6 ratio of 5.7.After the administration of a single dose, no significant differences between the two groups were observed. After repeated administration, significant differences could be detected in hemorheology, coagulation and elimination (p<0.01). The larger C2/C6 ratio led to a higher intravascular mean molecular weight (95 vs. 84 kD), which in turn led to a higher increase in serum concentration during the therapy (14.7 vs.8.6 mg/ml). Hematocrit was lowered more (-30,5 vs. -23,5%) and plasma viscosity was increased more. There was also a more pronounced increase in partial thromboplastin time (+30% vs. +13%) and a factor of 2 larger decrease of factor VIII/von Willebrand factor-complex (p <0.01), which exceeded the dilution effect.The higher C2/C6 ratio of HES 200/0.5/13.4 slows down enzymatic degradation. After repeated administration of this starch, large molecules accumulate which are inefficiently degraded. The same effect has been observed after therapy with highly-substituted HES. This accumulation of large molecules leads to a beneficial longer lasting volume effect. The disadvantages include an increase in plasma viscosity and coagulation disturbances, which cannot be explained with the respective dilution effect alone. For these reasons, the C2/C6 ratio is of clinical relevance and should be included in the product labeling in the future.

Low Molecular Weight Heparin Therapy: Is Monitoring Needed?

1994 ◽  
Vol 72 (03) ◽  
pp. 330-334 ◽  
Author(s):  
B Boneu
Keyword(s):  
Molecular Weight ◽  
Clinical Trials ◽  
Plasma Proteins ◽  
Bleeding Risk ◽  
Heparin Therapy ◽  
Low Molecular Weight ◽  
Vein Thrombosis ◽  
Meta Analyses ◽  
Deep Vein ◽  
Initial Check

SummaryRecent meta-analyses indicate that low molecular weight heparins (LMWH) are more effective than unfractionated heparin (UH) in preventing and treating deep vein thrombosis. This article presents the arguments for and against the need for laboratory monitoring. At the present time, the only tests currently available for monitoring LMWH therapy are those which measure the anti Xa activity in the plasma. Due to lower binding to plasma proteins and to cell surfaces,the plasma anti Xa activity generated by a given dose of LMWH is more predictable than for UH.Some clinical trials suggest that LMWH delivered at the recommended dose expose the patient to less bleeding risk than UH. Several . meta-analyses indicate comparable risk while any overdose unaccept-ably increases the haemorrhagic risk. The lowest dose of LMWH still effective in treating established DVT is presently unknown; some reports indicate that inadequate doses of LMWH are associated with a lack of efficacy for prevention. An overview of the published clinical trials indicates that the LMWH dose has never been monitored for prevention of DVT. In the treatment of established DVT, several trials have been performed without any monitoring, while in others the dose was adapted to target a given anti Xa activity. These considerations suggest that in prevention of DVT, monitoring the dose is not required. In the treatment of established DVT, considering the haemorrhagic risk of LMWH, the risk of undertreating the patient and the absence of large clinical trials comparing the advantages of monitoring the dose or not, it might be useful to check anti Xa activity at least once at the beginning of the treatment but the need for this initial check remains to be established. Because a large proportion of patients will be in the desired range, dose adjustments will be far less frequent than for UH.

PO-97 Overall survival with warfarin versus low-molecular-weight heparin in cancer-associated thrombosis

2021 ◽  
Vol 200 ◽  
pp. S72-S73
Author(s):  
R. Patell ◽  
T. Chiasakul ◽  
R. Redd ◽  
A.M. Khan ◽  
E.P. McCarthy ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Overall Survival ◽  
Low Molecular Weight Heparin ◽  
Low Molecular Weight ◽  
Cancer Associated Thrombosis

scholarly journals G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer

2020 ◽  
Vol 180 (3) ◽  
pp. 635-646 ◽  
Author(s):  
Kaitlyn J. Andreano ◽  
Suzanne E. Wardell ◽  
Jennifer G. Baker ◽  
Taylor K. Desautels ◽  
Robert Baldi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Animal Models ◽  
Tumor Growth ◽  
Inhibit Tumor Growth

New Oral Anticoagulants Versus Low Molecular Weight Heparins for the Treatment of Cancer-associated Thrombosis: a Cost-effectiveness Analysis

2021 ◽  
Author(s):  
Kaidireyahan Wumaier ◽  
Wenqian Li ◽  
Naifei Chen ◽  
Jiuwei Cui
Keyword(s):  
Molecular Weight ◽  
Cost Effectiveness ◽  
Oral Anticoagulants ◽  
New Oral Anticoagulants ◽  
Low Molecular Weight ◽  
Test Model ◽  
Low Molecular Weight Heparins ◽  
Gastrointestinal Malignancy ◽  
Cancer Associated Thrombosis ◽  
The Cost

Abstract Background: Recently, new oral anticoagulants (NOACs) have been included in guidelines for the treatment of cancer-associated thrombosis (CAT) to be extended to suitable cancer patients. The purpose of this study was to compare the cost-effectiveness of using NOACs and low molecular weight heparins(LMWHs) for treating CAT from the perspective of the Chinese healthcare system. Methods: A Markov model was constructed to estimate the cost-effectiveness of the two strategies with a 6-month and 5-year time horizon. Input parameters were either sourced from the clinical trial, published literature. The primary outcome of the model was reported as incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were performed to test model uncertainty. Results: The 6-month cost of NOACs was $ 654.65 with 0.40 QALYs while the 6-month cost of LMWHs was $ 1719.31 with 0.37 QALYs. Similarly, treatment with NOACs had a lower cost ($ 657.85 vs. $ 1716.56) and more health benefits (0.40 QALY vs. 0.37 QALY) than treatment with LMWHs in a subgroup of patients with gastrointestinal malignancy. We found treatment with NOACs would result in a large reduction in cost($ 1447.22 vs. $ 3374.70) but a small reduction in QALYs (3.07 QALY vs. 3.09 QALY) compared with LMWHs over a 5-year time frame, resulting in an ICER of $ 112895.50/QALY. Sensitivity analysis confirmed the robustness of the results. Conclusion: As compared to LMWHs, NOACs can be a cost-saving anticoagulant choice for the treatment of CAT in the general oncology population and gastrointestinal malignancy population.Classification codes: I.

Sign in / Sign up

Export Citation Format

Share Document