Studies in Man and Experimental Animals of a Low Molecular Weight Heparin Fraction

1981 ◽  
Vol 45 (03) ◽  
pp. 214-218 ◽  
Author(s):  
D P Thomas ◽  
R E Merton ◽  
W E Lewis ◽  
T W Barrowcliffe
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Specific Activity ◽  
Ex Vivo ◽  
High Specific Activity ◽  
Factor Xa ◽  
In Vivo Studies ◽  
Low Molecular Weight

SummaryIn vitro and in vivo studies were carried out on a commercially prepared low molecular weight heparin fraction. By APTT assay the fraction had a specific activity of half that of unfractionated mucosal heparin, yet retained full potency by anti-Xa assay (both clotting and chromogenic substrate). When administered intravenously to human volunteers, the anti-Xa/APTT ratio remained the same as it was in vitro. However, after subcutaneous injection, the ratio increased and anti-Xa activity could not be fully neutralized ex vivo by PF4. The fraction was as effective as unfractionated heparin in preventing experimental serum-induced thrombosis, suggesting that a heparin fraction with high specific activity by anti-Factor Xa assay compared to APTT activity may be an effective drug for the prophylaxis of venous thrombosis.

Effects of Unfractionated and Low Molecular Weight Heparins on Platelet Thromboxane Biosynthesis “In Vivo”

1994 ◽  
Vol 72 (06) ◽  
pp. 942-946 ◽  
Author(s):  
Raffaele Landolfi ◽  
Erica De Candia ◽  
Bianca Rocca ◽  
Giovanni Ciabattoni ◽  
Armando Antinori ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Primary Source ◽  
In Vivo Studies ◽  
Low Molecular Weight ◽  
Heparin Administration ◽  
To Receive

SummarySeveral “in vitro” and “in vivo” studies indicate that heparin administration may affect platelet function. In this study we investigated the effects of prophylactic heparin on thromboxane (Tx)A2 biosynthesis “in vivo”, as assessed by the urinary excretion of major enzymatic metabolites 11-dehydro-TxB2 and 2,3-dinor-TxB2. Twenty-four patients who were candidates for cholecystectomy because of uncomplicated lithiasis were randomly assigned to receive placebo, unfractionated heparin, low molecular weight heparin or unfractionaed heparin plus 100 mg aspirin. Measurements of daily excretion of Tx metabolites were performed before and during the treatment. In the groups assigned to placebo and to low molecular weight heparin there was no statistically significant modification of Tx metabolite excretion while patients receiving unfractionated heparin had a significant increase of both metabolites (11-dehydro-TxB2: 3844 ± 1388 vs 2092 ±777, p <0.05; 2,3-dinor-TxB2: 2737 ± 808 vs 1535 ± 771 pg/mg creatinine, p <0.05). In patients randomized to receive low-dose aspirin plus unfractionated heparin the excretion of the two metabolites was largely suppressed thus suggesting that platelets are the primary source of enhanced thromboxane biosynthesis associated with heparin administration. These data indicate that unfractionated heparin causes platelet activation “in vivo” and suggest that the use of low molecular weight heparin may avoid this complication.

Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1356-1363 ◽  
Author(s):  
Barbara P. Schick ◽  
David Maslow ◽  
Adrianna Moshinski ◽  
James D. San Antonio
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Tandem Repeats ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Heparin Binding ◽  
High Affinity ◽  
Binding Peptides

Abstract Patients given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for prophylaxis or treatment of thrombosis sometimes suffer serious bleeding. We showed previously that peptides containing 3 or more tandem repeats of heparin-binding consensus sequences have high affinity for LMWH and neutralize LMWH (enoxaparin) in vivo in rats and in vitro in citrate. We have now modified the (ARKKAAKA)n tandem repeat peptides by cyclization or by inclusion of hydrophobic tails or cysteines to promote multimerization. These peptides exhibit high-affinity binding to LMWH (dissociation constant [Kd], ≈ 50 nM), similar potencies in neutralizing anti–Factor Xa activity of UFH and enoxaparin added to normal plasma in vitro, and efficacy equivalent to or greater than protamine. Peptide (ARKKAAKA)3VLVLVLVL was most effective in all plasmas from enoxaparin-treated patients, and was 4- to 20-fold more effective than protamine. Several other peptide structures were effective in some patients' plasmas. All high-affinity peptides reversed inhibition of thrombin-induced clot formation by UFH. These peptides (1 mg/300 g rat) neutralized 1 U/mL anti–Factor Xa activity of enoxaparin in rats within 1 to 2 minutes. Direct blood pressure and heart rate measurements showed little or no hemodynamic effect. These heparin-binding peptides, singly or in combination, are potential candidates for clinical reversal of UFH and LMWH in humans.

Novel Design of Peptides to Reverse the Anticoagulant Activities of Heparin and other Glycosaminoglycans

2001 ◽  
Vol 85 (03) ◽  
pp. 482-487 ◽  
Author(s):  
Joel Gradowski ◽  
James San Antonio ◽  
Jose Martinez ◽  
Barbara Schick
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Heparin Binding ◽  
Antifactor Xa ◽  
Novel Design

SummaryPatients undergoing anticoagulation with unfractionated heparin, low molecular weight heparin, or danaparoid may experience excess bleeding which requires reversal of the anticoagulant agent. Protamine is at present the only agent available for reversal of unfractionated heparin. Protamine is not effective in patients who have received low molecular weight heparin or danaparoid. We have developed a series of peptides based on consensus heparin binding sequences (Verrecchio et al., J Biol Chem 2000; 275: 7701-7707) that are capable of neutralizing the anti-thrombin activity of unfractionated heparin in vitro, the antifactor Xa activity of unfractionated heparin, Enoxaparin (Lovenox) and danaparoid (Orgaran) in vitro and the anti-Factor Xa activity of Enoxaparin in vivo in rats. These peptides may serve as alternatives for Protamine reversal of UFH and may be useful for neutralization of enoxaparin and danaparoid in humans.

A new low molecular weight heparin derivative. In vitro and in vivo studies

1983 ◽  
Vol 31 (4) ◽  
pp. 611-621 ◽  
Author(s):  
Martine Aiach ◽  
Anne Michaud ◽  
Jean-Luc Balian ◽  
M. Lefebvre ◽  
M. Woler ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
In Vivo Studies ◽  
Low Molecular Weight ◽  
Heparin Derivative

Significant Differences in Neutralization of Heparin and Its Low Molecular Fragments by Protamine Sulfate: An In Vivo Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1850-1850
Author(s):  
Mark A. Crowther ◽  
Klement Petr ◽  
Liao Peng ◽  
Chen Frank ◽  
Berry B. Leslie ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Factor Xa ◽  
In Vivo Model ◽  
Low Molecular Weight ◽  
Protamine Sulphate ◽  
Heparin Plasma ◽  
Optimal Regimen

Abstract In clinical practice, patients receiving low molecular weight heparin (LMWH) occasionally suffer bleeding. Protamine sulphate (PS) is often used to reverse the anticoagulant effect of LMWH in such cases. However, the optimal regimen of PS for complete neutralization of LMWH fragments has not been established. Results from our previous in vitro studies indicate that the ability of PS to neutralize LMWHs is inversely related to the charge of the low molecular weight heparin molecule; more heavily charged LMWHs (such as Tinzaparin) are more readily neutralized than less charged LMWHs (such as Enoxaparin). The aim of the current study was to confirm these findings using an in vivo model. Twenty minutes after administration of either saline, unfractionated heparin [UFH, 100U/kg], Tinzaparin [100U/kg] or enoxaparin [100U/kg], 50% of anesthetized rabbits received either saline or PS [1 mg/100 U of heparin or LMWH]. The efficacy of PS neutralization was assessed by serial measurements of anti-factor Xa heparin plasma levels. Results are presented as mean of the anti-factor Xa heparin activities normalized to the level at 10 minutes and summarized in the table below. As expected, PS completely neutralized the anti-factor Xa effect of UFH. However, PS was significantly less effective for neutralization of Tinzaparin (about 66%) and Enoxaparin (about 44%) at the dose tested. We conclude that when tested in an in vivo model LMWHs vary in their protamine neutralizability. More highly charged LMWHs (e.g. Tinazaparin) are more neutralizable than less highly charged products (e.g. Enoxaparin). Residual Anti-Xa heparin effect Time Enoxaparin Tinzaparin UFH Saline + PS Enoxaparin +PS Tinzaparin + PS UFH + PS 10 min 1.00 1.00 1.00 0 1.00 1.00 1.00 20 min 0.85 0.86 0.70 0 0.80 0.85 0.89 Protamine 25 min 0.71 0.75 0.69 0 0.45 0.29 0.01 35 min 0.68 0.64 0.48 0 0.40 0.28 0 50 min 0.48 0.32

scholarly journals NOVEL NANOPARTICLES FOR THE ORAL DELIVERY OF LOW MOLECULAR WEIGHT HEPARIN: IN VITRO AND IN VIVO ASSESSMENT

2017 ◽  
Vol 10 (2) ◽  
pp. 254 ◽  
Author(s):  
Nallaguntla Lavanya ◽  
Indira Muzib ◽  
Aukunuru Jithan ◽  
Balekari Umamahesh
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Ex Vivo ◽  
In Vitro Release ◽  
Low Molecular Weight ◽  
Scanning Calorimetry ◽  
Ex Vivo Permeation ◽  
Permeation Studies

Objective: The objective of the present study was to prepare and evaluate a novel oral formulation of nanoparticles for the systemic delivery of low molecular weight heparin (LMWH). Methods: Nanoparticles were prepared by polyelectrolyte complexation (PEC) method using polymers sodium alginate and chitosan. Entrapment efficiency of LMWH in nanoparticles was found to be  ̴88%. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X‑ray diffraction (XRD), Scanning electron microscopy (SEM)  studies carried for nanoparticles. In vitro release studies were performed for the formulations. Ex vivo permeation studies were performed optimized formulation by using small intestine of rat and in vivo studies were conducted on rat model.Results: In vitro release studies demonstrated that the release of LMWH was negligible in the stomach and high in the small intestine. FTIR has indicated that there is no interaction between the ingredients in nanoparticle. DSC and XRD studies confirmed that the amino groups of chitosan interacted with the carboxylic groups of alginate. Invitro % drug release of 95% was shown by formulation AC5. Ex vivo permeation studies have elucidated that ̴ 73% of LMWH was transported across the epithelium. Nanoparticles have shown enhanced oral bioavailability of LMWH as revealed by 4.5 fold increase in AUC of plasma drug concentration time curve.Conclusion: The results suggest that the nanoparticles prepared can result in targeted delivery of LMWH into systemic circulation via intestinal and colon routes. Novel nanoparticles thus prepared in this study can be considered as a promising delivery system.Keywords: Antifactor Xa activity, Chitosan, Differential scanning calorimetry, Sodium alginate, Low-molecular-weight heparin, Oral bioavailability.

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