Absorption and antithrombotic activity of unfractioned heparin after intraduodenal administration in rats

Costantini, Vincenzo; Deveglia, R.; Stabile, Anna Maria; Gg, Nenci

doi:10.1097/00001721-200001000-00002

Cited by 9 publications

(6 citation statements)

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“…Both UFH and LMWH in drinking water, given to spontaneously hypertensive rats, returned systolic blood pressure to normal (23). Thrombosis was prevented by oral UFH and LMWHs in the rat jugular vein (6,8,9,14), carotid artery (4), and venous stasis models (3,24).…”

Section: Discussionmentioning

confidence: 99%

Movement of Heparins Across Rat Gastric Mucosa is Dependent on Molecular Weight and pH

Moazed

Hiebert

2008

Pharm Res

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Section: Discussionmentioning

confidence: 99%

Movement of Heparins Across Rat Gastric Mucosa is Dependent on Molecular Weight and pH

Moazed

Hiebert

2008

Pharm Res

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“…If concentrations of heparin with endothelium in these vessels were applied to endothelium in the whole body, it was calculated that considerable amounts of the total heparin administered could be found with the endothelium (Jaques et al, 1991;Hiebert et al, 1993). 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).…”

Section: Discussionmentioning

confidence: 99%

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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“…Numerous attempts have been made to develop an oral delivery system for heparins both in vitro and in vivo. In vivo studies involved different animal models such as mice [40,41], rat [42][43][44][45][46][47][48][49][50][51][52][53][54][55], rabbit [56][57][58], dog [59], pig [53], primates [48] and human [60][61][62][63][64][65]. Table 2 underlines examples of oral formulation tested in humans.…”

Section: Heparin Containing Dds For Oral Routementioning

confidence: 99%

The quest for non-invasive delivery of bioactive macromolecules: A focus on heparins

Motlekar

Youan

2006

Journal of Controlled Release

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The development of a non-invasive drug delivery system for unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) has been the elusive goal of several research groups since the initial discovery of this glycosaminogylcan by McLean in 1916. After a brief update on current parenteral formulations of UFH and LMWHs, this review revisits past and current strategies intended to identify alternative routes of administration (e.g. oral, sublingual, rectal, nasal, pulmonary and transdermal). The following strategies have been used to improve the bioavailability of this bioactive macromolecule by various routes: (i) enhancement in cell-membrane permeabilization, (ii) modification of the tight-junctions, (iii) increase in lipophilicity and (iv) protection against acidic pH of the stomach. Regardless of the route of administration, a simplified unifying principle for successful non-invasive macromolecular drug delivery may be: "to reversibly overcome the biological, biophysical and biochemical barriers and to safely and efficiently improve the in vivo spatial and temporal control of the drug in order to achieve a clinically acceptable therapeutic advantage". Future macromolecular drug delivery research should embrace a more systemic approach taking into account recent advances in genomics/proteomics and nanotechnology.

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Absorption and antithrombotic activity of unfractioned heparin after intraduodenal administration in rats

Cited by 9 publications

References 0 publications

Movement of Heparins Across Rat Gastric Mucosa is Dependent on Molecular Weight and pH

Movement of Heparins Across Rat Gastric Mucosa is Dependent on Molecular Weight and pH

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

The quest for non-invasive delivery of bioactive macromolecules: A focus on heparins

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