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Jean-j Thebault - One of the best experts on this subject based on the ideXlab platform.
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comparison of the pharmacokinetic profiles of three low molecular mass heparins dalteparin enoxaparin and Nadroparin administered subcutaneously in healthy volunteers doses for prevention of thromboembolism
Thrombosis and Haemostasis, 1995Co-Authors: F Collignon, Aviad Frydman, H Caplain, M L Ozoux, Le Roux Y, Jd Bouthier, Jean-j ThebaultAbstract:Abstract The present trial was designed to comparatively investigate the pharmacokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins (LMMHs): dalteparin (Fragmin), Nadroparin (Fraxiparin), and enoxaparin (Lovenox) given by subcutaneous route. The study was carried out in 20 healthy young volunteers given, according to a cross over design, a single subcutaneous injection of the doses recommended for the prophylaxis of deep vein thrombosis (commercial preparations, prefilled syringes): dalteparin 2,500 IU (= 2,500 IU anti-Xa), Nadroparin 7,500 ICU (= 3,075 IU anti-Xa), enoxaparin 20 mg (= 2,000 IU anti-Xa) and enoxaparin 40 mg (= 4,000 IU anti-Xa). Of the markers used, activated partial thromboplastin time (APTT), thrombin clotting time (TCT), Heptest, anti-thrombin (aIIa) activity and anti-Xa (aXa) activity, the most pertinent parameter (from a biodynamic viewpoint) is plasma aXa activity. We demonstrated that dalteparin, Nadroparin and enoxaparin exhibit statistically significantly different pharmacokinetic and overall disposition patterns. Normalized to the same injected dose (1,000 IU aXa), the relative actual amount of plasma anti-Xa activity generated by enoxaparin is 1.48 times greater (p < 0.001) than that of Nadroparin and 2.28 times greater (p < 0.001) than that of dalteparin while the plasma amount induced by Nadroparin is 1.54 times greater (p < 0.001) than that of dalteparin. The apparent total body clearance of enoxaparin doses (CL/F = 16.7 +/- 5.5 and 13.8 +/- 3.2 ml/min) is significantly smaller than those of Nadroparin (CL/F = 21.4 +/- 7.0 ml/min; p < 0.01) and dalteparin (CL/F = 33.3 +/- 11.8 ml/min; p < 0.001) while dalteparin apparent clearance is about 1.5-fold greater (p < 0.001) than that of Nadroparin. These LMMHs also differ by their renal excretion pattern: more fragments exhibiting an anti-Xa activity are recovered in urine following enoxaparin doses (6.4 and 8.7% of the dose, respectively) than following Nadroparin (3.9%) and dalteparin (3.4%) injection. These differences in the disposition profiles explain why the apparent elimination half life t1/2 values of the LMMHs compared here are different: dalteparin: 2.8 h; Nadroparin: 3.7 h; and enoxaparin: 4.1 h. Whether or not these differences may contribute to explain the different safety/efficacy balance of each of these antithrombotic medications remains to be discussed and needs further studies.
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comparison of the pharmacokinetic profiles of three low molecular mass heparins dalteparin enoxaparin and Nadroparin administered subcutaneously in healthy volunteers doses for prevention of thromboembolism
Thrombosis and Haemostasis, 1995Co-Authors: F Collignon, Aviad Frydman, H Caplain, M L Ozoux, Jd Bouthier, Le Y Roux, Jean-j ThebaultAbstract:The present trial was designed to comparatively investigate the pharmacokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins (LMMHs): dalteparin (Fragmin®), Nadroparin (Fraxiparin®), and enoxaparin (Love- nox®) given by subcutaneous route. The study was carried out in 20 healthy young volunteers given, according to a cross over design, a single subcutaneous injection of the doses recommended for the prophylaxis of deep vein thrombosis (commercial preparations, prefilled syringes): dalteparin 2,500 IU (= 2,500 IU anti-Xa), Nadroparin 7,500 ICU (= 3,075 IU anti-Xa), enoxaparin 20 mg (= 2,000 IU anti-Xa) and enoxaparin 40 mg (= 4,000 IU anti-Xa). Of the markers used, activated partial thromboplastin time (APTT), thrombin clotting time (TCT), Heptest®, anti-thrombin (aIIa) activity and anti-Xa (aXa) activity, the most pertinent parameter (from a biodynamic viewpoint) is plasma aXa activity. We demonstrated that dalteparin, Nadroparin and enoxaparin exhibit statistically significantly different pharmacokinetic and overall disposition patterns. Normalized to the same injected dose (1,000 IU aXa), the relative actual amount of plasma anti-Xa activity generated by enoxaparin is 1.48 times greater (p
F Collignon - One of the best experts on this subject based on the ideXlab platform.
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comparison of the pharmacokinetic profiles of three low molecular mass heparins dalteparin enoxaparin and Nadroparin administered subcutaneously in healthy volunteers doses for prevention of thromboembolism
Thrombosis and Haemostasis, 1995Co-Authors: F Collignon, Aviad Frydman, H Caplain, M L Ozoux, Le Roux Y, Jd Bouthier, Jean-j ThebaultAbstract:Abstract The present trial was designed to comparatively investigate the pharmacokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins (LMMHs): dalteparin (Fragmin), Nadroparin (Fraxiparin), and enoxaparin (Lovenox) given by subcutaneous route. The study was carried out in 20 healthy young volunteers given, according to a cross over design, a single subcutaneous injection of the doses recommended for the prophylaxis of deep vein thrombosis (commercial preparations, prefilled syringes): dalteparin 2,500 IU (= 2,500 IU anti-Xa), Nadroparin 7,500 ICU (= 3,075 IU anti-Xa), enoxaparin 20 mg (= 2,000 IU anti-Xa) and enoxaparin 40 mg (= 4,000 IU anti-Xa). Of the markers used, activated partial thromboplastin time (APTT), thrombin clotting time (TCT), Heptest, anti-thrombin (aIIa) activity and anti-Xa (aXa) activity, the most pertinent parameter (from a biodynamic viewpoint) is plasma aXa activity. We demonstrated that dalteparin, Nadroparin and enoxaparin exhibit statistically significantly different pharmacokinetic and overall disposition patterns. Normalized to the same injected dose (1,000 IU aXa), the relative actual amount of plasma anti-Xa activity generated by enoxaparin is 1.48 times greater (p < 0.001) than that of Nadroparin and 2.28 times greater (p < 0.001) than that of dalteparin while the plasma amount induced by Nadroparin is 1.54 times greater (p < 0.001) than that of dalteparin. The apparent total body clearance of enoxaparin doses (CL/F = 16.7 +/- 5.5 and 13.8 +/- 3.2 ml/min) is significantly smaller than those of Nadroparin (CL/F = 21.4 +/- 7.0 ml/min; p < 0.01) and dalteparin (CL/F = 33.3 +/- 11.8 ml/min; p < 0.001) while dalteparin apparent clearance is about 1.5-fold greater (p < 0.001) than that of Nadroparin. These LMMHs also differ by their renal excretion pattern: more fragments exhibiting an anti-Xa activity are recovered in urine following enoxaparin doses (6.4 and 8.7% of the dose, respectively) than following Nadroparin (3.9%) and dalteparin (3.4%) injection. These differences in the disposition profiles explain why the apparent elimination half life t1/2 values of the LMMHs compared here are different: dalteparin: 2.8 h; Nadroparin: 3.7 h; and enoxaparin: 4.1 h. Whether or not these differences may contribute to explain the different safety/efficacy balance of each of these antithrombotic medications remains to be discussed and needs further studies.
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comparison of the pharmacokinetic profiles of three low molecular mass heparins dalteparin enoxaparin and Nadroparin administered subcutaneously in healthy volunteers doses for prevention of thromboembolism
Thrombosis and Haemostasis, 1995Co-Authors: F Collignon, Aviad Frydman, H Caplain, M L Ozoux, Jd Bouthier, Le Y Roux, Jean-j ThebaultAbstract:The present trial was designed to comparatively investigate the pharmacokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins (LMMHs): dalteparin (Fragmin®), Nadroparin (Fraxiparin®), and enoxaparin (Love- nox®) given by subcutaneous route. The study was carried out in 20 healthy young volunteers given, according to a cross over design, a single subcutaneous injection of the doses recommended for the prophylaxis of deep vein thrombosis (commercial preparations, prefilled syringes): dalteparin 2,500 IU (= 2,500 IU anti-Xa), Nadroparin 7,500 ICU (= 3,075 IU anti-Xa), enoxaparin 20 mg (= 2,000 IU anti-Xa) and enoxaparin 40 mg (= 4,000 IU anti-Xa). Of the markers used, activated partial thromboplastin time (APTT), thrombin clotting time (TCT), Heptest®, anti-thrombin (aIIa) activity and anti-Xa (aXa) activity, the most pertinent parameter (from a biodynamic viewpoint) is plasma aXa activity. We demonstrated that dalteparin, Nadroparin and enoxaparin exhibit statistically significantly different pharmacokinetic and overall disposition patterns. Normalized to the same injected dose (1,000 IU aXa), the relative actual amount of plasma anti-Xa activity generated by enoxaparin is 1.48 times greater (p
Javot Lucie - One of the best experts on this subject based on the ideXlab platform.
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Etude in vitro et in vivo de deux héparines de bas poids moléculaire microencapsulées de rapports anti-Xa/anti-IIa différents (la Nadroparine et la tinzaparine)
2009Co-Authors: Javot Lucie, Maincent Philippe, Lecompte ThomasAbstract:Des microparticules d héparine de bas poids moléculaire (HBPM) ont été fabriquées suivant la méthode de la double émulsion à partir d un polymère non biodégradable polycationique (Eudragit® RS) utilisé seul ou en mélange à différents pourcentages avec un polymère biodégradable (acide poly(lactique-co-glycolique)). Deux HBPM aux rapports anti-Xa/anti-IIa différents ont été testées : la Nadroparine (3,6) et la tinzaparine (1,8). Les microparticules d HBPM favorisent i) l encapsulation des chaines longues actives (ACL) d héparine par rapport aux chaines courtes actives (BCL) (diminution du rapport anti-Xa/anti-IIa) ii) la libération in vitro des chaines BCL (augmentation du rapport anti-Xa/anti-IIa), les chaines ACL étant fortement retenues au sein des microparticules. Cependant, la proportion de chaine BCL libérées par rapport à celle d ACL est dépendante (cas de la Nadroparine) ou non (cas de la tinzaparine) de la composition polymérique. Cette différence de comportement s explique principalement par la capacité de l Eudragit® RS à retenir les chaines ACL de Nadroparine. Suite à l administration orale de microparticules de Nadroparine chez le lapin, une absorption des chaines ACL et BCL a été mise en évidence avec certaines formulations : dans ce cas, des rapports anti-Xa/anti-IIa plasmatique similaires à ceux résultant de l injection sous-cutanée ont été obtenus, témoignant ainsi du potentiel de ces microparticules à remplacer la forme commerciale injectable. Lors d études de localisation par microscopie confocale, le site d absorption intestinal n a pas été identifié. En revanche, des études de passage sur un épithélium issu de la culture cellulaire (Caco-2) semblent démontrer, contrairement aux résultats in vivo, que seules les chaines BCL de Nadroparine seraient absorbées. Cependant, le mécanisme responsable du passage cellulaire reste à identifier.Microparticles of low molecular weight heparin (LMWH) were prepared according to the double emulsion and extraction method using a non biodegradable polycationic polymer (Eudragit® RS) alone or blended according to different ratios with a biodegradable polymer (poly(lactic-co-glycolic) acid). Two LMWH presenting different anti-Xa/anti-IIa ratios were tested: Nadroparin (3.6) and tinzaparin (1.8). LMWH microparticles facilitate i) the encapsulation of heparin active long chains (ACL) compared to active short chains (BCL) (anti-Xa/anti-IIa ratio decreased) ii) the in vitro release of short chains (anti-Xa/anti-IIa ratio increased) whereas long chains are held inside the microparticles. Nevertheless, when compared to ACL chains, the relative amount of BCL chains released is dependent (case of Nadroparine) or not (case of tinzaparin) on the polymeric composition. This difference can be mainly due to the properties of Eudragit® RS to hold ACL chains of Nadroparin. After an oral administration in rabbits of Nadroparin microparticles, some formulations exhibited absorption of ACL and BCL chains: in this case, plasmatic anti-Xa/anti-IIa ratios in the same range than those observed following the subcutaneous injection were obtained. Such a result shows the potential of microparticles to be a good substitute of the commercial injectable dosage form, if the oral absorption is confirmed in human. During gastro-intestinal studies by confocal microscopy, the absorption site was not identified. Nevertheless, contrary to in vivo results, permeation studies on a cell cultured epithelium (Caco-2) demonstrated that BCL heparin chains were absorbed whereas ACL chains were not. However, the mechanism responsible of the cell permeation is still to be identified.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF
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Etude in vitro et in vivo de deux héparines de bas poids moléculaire microencapsulées de rapports anti-Xa/anti-IIa différents : la Nadroparine et la tinzaparine
2009Co-Authors: Javot LucieAbstract:Des microparticules d’héparine de bas poids moléculaire (HBPM) ont été fabriquées suivant la méthode de la double émulsion à partir d’un polymère non biodégradable polycationique (Eudragit® RS) utilisé seul ou en mélange à différents pourcentages avec un polymère biodégradable (acide poly(lactique-co-glycolique)). Deux HBPM aux rapports anti-Xa/anti-IIa différents ont été testées : la Nadroparine (3,6) et la tinzaparine (1,8). Les microparticules d’HBPM favorisent i) l’encapsulation des chaines longues actives (ACL) d’héparine par rapport aux chaines courtes actives (BCL) (diminution du rapport anti-Xa/anti-IIa) ii) la libération in vitro des chaines BCL (augmentation du rapport anti-Xa/anti-IIa), les chaines ACL étant fortement retenues au sein des microparticules. Cependant, la proportion de chaine BCL libérées par rapport à celle d’ACL est dépendante (cas de la Nadroparine) ou non (cas de la tinzaparine) de la composition polymérique. Cette différence de comportement s’explique principalement par la capacité de l’Eudragit® RS à retenir les chaines ACL de Nadroparine. Suite à l’administration orale de microparticules de Nadroparine chez le lapin, une absorption des chaines ACL et BCL a été mise en évidence avec certaines formulations : dans ce cas, des rapports anti-Xa/anti-IIa plasmatique similaires à ceux résultant de l’injection sous-cutanée ont été obtenus, témoignant ainsi du potentiel de ces microparticules à remplacer la forme commerciale injectable. Lors d’études de localisation par microscopie confocale, le site d’absorption intestinal n’a pas été identifié. En revanche, des études de passage sur un épithélium issu de la culture cellulaire (Caco-2) semblent démontrer, contrairement aux résultats in vivo, que seules les chaines BCL de Nadroparine seraient absorbées. Cependant, le mécanisme responsable du passage cellulaire reste à identifier.Microparticles of low molecular weight heparin (LMWH) were prepared according to the double emulsion and extraction method using a non biodegradable polycationic polymer (Eudragit® RS) alone or blended according to different ratios with a biodegradable polymer (poly(lactic-co-glycolic) acid). Two LMWH presenting different anti-Xa/anti-IIa ratios were tested: Nadroparin (3.6) and tinzaparin (1.8). LMWH microparticles facilitate i) the encapsulation of heparin active long chains (ACL) compared to active short chains (BCL) (anti-Xa/anti-IIa ratio decreased) ii) the in vitro release of short chains (anti-Xa/anti-IIa ratio increased) whereas long chains are held inside the microparticles. Nevertheless, when compared to ACL chains, the relative amount of BCL chains released is dependent (case of Nadroparine) or not (case of tinzaparin) on the polymeric composition. This difference can be mainly due to the properties of Eudragit® RS to hold ACL chains of Nadroparin. After an oral administration in rabbits of Nadroparin microparticles, some formulations exhibited absorption of ACL and BCL chains: in this case, plasmatic anti-Xa/anti-IIa ratios in the same range than those observed following the subcutaneous injection were obtained. Such a result shows the potential of microparticles to be a good substitute of the commercial injectable dosage form, if the oral absorption is confirmed in human. During gastro-intestinal studies by confocal microscopy, the absorption site was not identified. Nevertheless, contrary to in vivo results, permeation studies on a cell cultured epithelium (Caco-2) demonstrated that BCL heparin chains were absorbed whereas ACL chains were not. However, the mechanism responsible of the cell permeation is still to be identified
O Pichot - One of the best experts on this subject based on the ideXlab platform.
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anticoagulant therapy for symptomatic calf deep vein thrombosis cactus a randomised double blind placebo controlled trial
The Lancet Haematology, 2016Co-Authors: Marc Philip Righini, Jeanphilippe Galanaud, Herve Guenneguez, D Brisot, Antoine Diard, Pascale Faisse, M T Barrellier, Claudine Hameldesnos, Christine Jurus, O PichotAbstract:Summary Background The efficacy and safety of anticoagulant treatment is not established for patients with acute symptomatic deep vein thrombosis (DVT) of the calf. We aimed to assess whether therapeutic anticoagulation is superior to placebo in patients with symptomatic calf DVT. Methods In this randomised, double-blind, placebo-controlled trial, we enrolled low-risk outpatients (without active cancer or previous venous thromboembolic disease) with a first acute symptomatic DVT in the calf from 23 university medical centres or community medical clinics in Canada, France, and Switzerland. We randomly assigned (1:1) patients to receive either the low-molecular-weight heparin Nadroparin (171 UI/kg, subcutaneously, once a day) or placebo (saline 0·9%, subcutaneously, once a day) for 6 weeks (42 days). Central randomisation was done using a computer-generated randomisation list, stratified by study centre. Random allocation sequences of variable block size were centrally determined by an independent research clinical centre. Study staff, patients, and outcome assessors (central adjudication committee) were masked to group assignment. Numbered boxes of active drug or placebo were provided to pharmacies in identical packaging. All patients were prescribed compression stockings and followed up for 90 days. The primary efficacy outcome was a composite measure of extension of calf DVT to proximal veins, contralateral proximal DVT, and symptomatic pulmonary embolism at day 42 in the modified intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding at day 42. The trial was registered with ClinicalTrials.gov, number NCT00421538. Findings Between Feb 1, 2008, and Nov 30, 2014, we screened 746 patients, enrolling 259 patients (50% of the prespecified sample size), before the trial steering committee terminated the trial because of expiry of study drug and slow recruitment. The intention-to-treat analysis population comprised 122 patients in the Nadroparin group and 130 in the placebo group. There was no significant difference between the groups in the composite primary outcome, which occurred in four patients (3%) in the Nadroparin group and in seven (5%) in the placebo group (risk difference −2·1%, 95% CI −7·8 to 3·5; p=0·54). Bleeding occurred in five patients (4%) in the Nadroparin group and no patients in the placebo group (risk difference 4·1, 95% CI 0·4 to 9·2; p=0·0255). In the Nadroparin group one patient died from metastatic pancreatic cancer and one patient was diagnosed with heparin-induced thrombocytopenia type 2. Interpretation Nadroparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with symptomatic calf DVT, but did increase the risk of bleeding. Avoidance of systematic anticoagulation for calf DVT could have a substantial impact on individual patients and from a public health perspective. Funding Swiss National Science Foundation, the Programme Hospitalier de Recherche Clinique in France, and the Canadian Institutes of Health Research.
Jd Bouthier - One of the best experts on this subject based on the ideXlab platform.
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comparison of the pharmacokinetic profiles of three low molecular mass heparins dalteparin enoxaparin and Nadroparin administered subcutaneously in healthy volunteers doses for prevention of thromboembolism
Thrombosis and Haemostasis, 1995Co-Authors: F Collignon, Aviad Frydman, H Caplain, M L Ozoux, Le Roux Y, Jd Bouthier, Jean-j ThebaultAbstract:Abstract The present trial was designed to comparatively investigate the pharmacokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins (LMMHs): dalteparin (Fragmin), Nadroparin (Fraxiparin), and enoxaparin (Lovenox) given by subcutaneous route. The study was carried out in 20 healthy young volunteers given, according to a cross over design, a single subcutaneous injection of the doses recommended for the prophylaxis of deep vein thrombosis (commercial preparations, prefilled syringes): dalteparin 2,500 IU (= 2,500 IU anti-Xa), Nadroparin 7,500 ICU (= 3,075 IU anti-Xa), enoxaparin 20 mg (= 2,000 IU anti-Xa) and enoxaparin 40 mg (= 4,000 IU anti-Xa). Of the markers used, activated partial thromboplastin time (APTT), thrombin clotting time (TCT), Heptest, anti-thrombin (aIIa) activity and anti-Xa (aXa) activity, the most pertinent parameter (from a biodynamic viewpoint) is plasma aXa activity. We demonstrated that dalteparin, Nadroparin and enoxaparin exhibit statistically significantly different pharmacokinetic and overall disposition patterns. Normalized to the same injected dose (1,000 IU aXa), the relative actual amount of plasma anti-Xa activity generated by enoxaparin is 1.48 times greater (p < 0.001) than that of Nadroparin and 2.28 times greater (p < 0.001) than that of dalteparin while the plasma amount induced by Nadroparin is 1.54 times greater (p < 0.001) than that of dalteparin. The apparent total body clearance of enoxaparin doses (CL/F = 16.7 +/- 5.5 and 13.8 +/- 3.2 ml/min) is significantly smaller than those of Nadroparin (CL/F = 21.4 +/- 7.0 ml/min; p < 0.01) and dalteparin (CL/F = 33.3 +/- 11.8 ml/min; p < 0.001) while dalteparin apparent clearance is about 1.5-fold greater (p < 0.001) than that of Nadroparin. These LMMHs also differ by their renal excretion pattern: more fragments exhibiting an anti-Xa activity are recovered in urine following enoxaparin doses (6.4 and 8.7% of the dose, respectively) than following Nadroparin (3.9%) and dalteparin (3.4%) injection. These differences in the disposition profiles explain why the apparent elimination half life t1/2 values of the LMMHs compared here are different: dalteparin: 2.8 h; Nadroparin: 3.7 h; and enoxaparin: 4.1 h. Whether or not these differences may contribute to explain the different safety/efficacy balance of each of these antithrombotic medications remains to be discussed and needs further studies.
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comparison of the pharmacokinetic profiles of three low molecular mass heparins dalteparin enoxaparin and Nadroparin administered subcutaneously in healthy volunteers doses for prevention of thromboembolism
Thrombosis and Haemostasis, 1995Co-Authors: F Collignon, Aviad Frydman, H Caplain, M L Ozoux, Jd Bouthier, Le Y Roux, Jean-j ThebaultAbstract:The present trial was designed to comparatively investigate the pharmacokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins (LMMHs): dalteparin (Fragmin®), Nadroparin (Fraxiparin®), and enoxaparin (Love- nox®) given by subcutaneous route. The study was carried out in 20 healthy young volunteers given, according to a cross over design, a single subcutaneous injection of the doses recommended for the prophylaxis of deep vein thrombosis (commercial preparations, prefilled syringes): dalteparin 2,500 IU (= 2,500 IU anti-Xa), Nadroparin 7,500 ICU (= 3,075 IU anti-Xa), enoxaparin 20 mg (= 2,000 IU anti-Xa) and enoxaparin 40 mg (= 4,000 IU anti-Xa). Of the markers used, activated partial thromboplastin time (APTT), thrombin clotting time (TCT), Heptest®, anti-thrombin (aIIa) activity and anti-Xa (aXa) activity, the most pertinent parameter (from a biodynamic viewpoint) is plasma aXa activity. We demonstrated that dalteparin, Nadroparin and enoxaparin exhibit statistically significantly different pharmacokinetic and overall disposition patterns. Normalized to the same injected dose (1,000 IU aXa), the relative actual amount of plasma anti-Xa activity generated by enoxaparin is 1.48 times greater (p
