Increased plasma anti-Xa activity and recovery of heparin from urine suggest absorption of orally administered unfractionated heparin in human subjects

Hiebert, Linda M.; Wice, Sandra M.; Ping, Tilly

doi:10.1016/j.lab.2005.01.006

Cited by 16 publications

(12 citation statements)

References 16 publications

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“…These studies are supported by the work of Engelberg who showed increases in APTT in a human study with oral heparin (28) and by our own studies showing an increase in anti-factor Xa activity and heparin in urine following a single dose of 7.5 mg/kg of heparin to human subjects (30). A recent study also confirms similar endothelial deposition of heparin as well as antithrombotic efficacy when administered orally in a rat model of carotid artery thrombosis (31).…”

Section: Discussionsupporting

confidence: 52%

In vivo antithrombotic synergy of oral heparin and arginine: Endothelial thromboresistance without changes in coagulation parameters

Daniels

Linhardt

Zhang³

et al. 2006

Thromb Haemost

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SummaryOn the basis of suggested clinical efficacy in an uncontrolled study in ninety-seven patients with unstable angina, an animal study was conducted to investigate antithrombotic synergy between orally administered heparin and arginine. A rat venous thrombosis model tested the difference in thrombus formation when heparin (7.5 mg/kg) and arginine (113 mg/kg) were administered, alone or in combination, by stomach tube with a minimum of 20 rats/group. Oral heparin, arginine, and heparin plus arginine reduced thrombus formation by 50%, 75%, and 90%, respectively, when compared to saline administration. Heparin was recovered from endothelium, yet there was little or no observable plasma anticoagulant activity. An orally administered low-molecular-weight anticoagulant glycosaminoglycan mixture, sulodexide (7.5 mg/kg), showed an 88% reduction in stable thrombus formation when administered alone but showed no synergy with oral arginine. A 28-day study with oral sulodexide (2.9 mg/ kg) and arginine (43.9 mg/kg), 20 rats/group, showed antithrombotic activity with minimal anticoagulant activity indicating suitability for long term treatment. These findings suggest the endothelial localization of heparin and a synergistic antithrombotic effect for orally administered heparin and arginine.

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Section: Discussionsupporting

confidence: 52%

In vivo antithrombotic synergy of oral heparin and arginine: Endothelial thromboresistance without changes in coagulation parameters

Daniels

Linhardt

Zhang³

et al. 2006

Thromb Haemost

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“…Although heparin is not considered effective when administered orally, results from our laboratory and others have shown evidence of oral heparin absorption (Hiebert et al, 1993(Hiebert et al, , 1996(Hiebert et al, , 2000(Hiebert et al, , 2001(Hiebert et al, , 2005Engelberg, 1995). Heparin was recovered from aortic and vena caval endothelium following oral administration of unfractionated heparin to rats.…”

Section: Discussionmentioning

confidence: 87%

“…Oral heparin was demonstrated to have antithrombotic activity in rat jugular vein (Hiebert et al, 2000(Hiebert et al, , 2001, venous stasis (Costantini et al, 2000), and carotid arterial thrombosis models (Pinel et al, 2004), further indicating that heparins are absorbed following oral administration. Evidence of heparin absorption was also seen in humans (Engelberg, 1995;Hiebert et al, 2005). Little is known about the site of heparin absorption.…”

Section: Discussionmentioning

confidence: 99%

“…As well, oral UFH and low molecular weight heparins significantly reduced thrombotic incidence in both rat jugular vein and carotid arterial models (Hiebert et al, 1996(Hiebert et al, , 2000(Hiebert et al, , 2001Pinel et al, 2004). Furthermore, an increase in plasma antifactor Xa (anti-Xa) activity and heparin in urine was observed in human subjects following oral administration (Hiebert et al, 2005). Therefore, these results suggest that heparin is absorbed following oral administration and that the oral route may be a feasible alternative for administering heparin.…”

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confidence: 94%

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An in Vitro Study with an Ussing Chamber Showing That Unfractionated Heparin Crosses Rat Gastric Mucosa

Moazed

Hiebert²

2007

J Pharmacol Exp Ther

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Heparin, traditionally given parenterally, is used to treat and prevent thrombosis. Our previous results suggest that orally administered unfractionated heparin (UFH) is absorbed and has antithrombotic effects. However, there is little evidence indicating the site and mechanism of heparin absorption. Our aim was to determine whether the stomach is an absorption site. Rat gastric mucosa was mounted in an Ussing chamber, and UFH was added to the mucosal buffer at pH 7.4. Potential difference (PD), resistance (R), and short circuit current (I sc ) across the mucosa were determined comparing the mucosal to the serosal side. Mucosal and serosal buffers and tissue were analyzed for chemical heparin and anticoagulant activity, antifactor Xa (anti-Xa) and antifactor IIa (anti-IIa) activity. The PD became more negative on UFH addition. Following a lag period, PD returned to the resting level. Changes in R followed those in PD, whereas I sc did not change. Heparin was found in the serosal and mucosal buffer and tissue. Heparin in the serosal buffer had anti-Xa and anti-IIa activity. Decreasing the pH of the mucosal buffer to 4.0, decreased the lag period for PD. Decreasing the concentration of UFH resulted in less pronounced changes in PD and less heparin in the serosal buffer. Changes in PD suggest that heparin moves across the mucosa. Presence of heparin in the serosal buffer and mucosal tissue, indicate that heparin crosses rat gastric mucosa. A stable I sc indicates passive diffusion contributes to heparin movement. The stomach could be a site for oral heparin absorption.

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“…Although evidence of heparin absorption was seen after oral administration in a recent study [49], this is insufficient to produce effective anticoagulation. A number of groups have attempted to develop modified forms of UFH or LMWH with improved oral absorption.…”

Section: Indirect Combined Thrombin and Activated Factor X Inhibitorsmentioning

confidence: 92%

New anticoagulants for venous thromboembolic disease

McRae

Ginsberg

2005

Current Opinion in Cardiology

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Increased plasma anti-Xa activity and recovery of heparin from urine suggest absorption of orally administered unfractionated heparin in human subjects

Cited by 16 publications

References 16 publications

In vivo antithrombotic synergy of oral heparin and arginine: Endothelial thromboresistance without changes in coagulation parameters

In vivo antithrombotic synergy of oral heparin and arginine: Endothelial thromboresistance without changes in coagulation parameters

An in Vitro Study with an Ussing Chamber Showing That Unfractionated Heparin Crosses Rat Gastric Mucosa

New anticoagulants for venous thromboembolic disease

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