Download PDF
Thromb Haemost 2001; 85(01): 114-118
DOI: 10.1055/s-0037-1612913
Review Article
Schattauer GmbH

Antithrombotic Efficacy in a Rat Model of the Low Molecular Weight Heparin, Reviparin Sodium, Administered by the Oral Route

Linda M. Hiebert
1   Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, Canada
,
Sandra M. Wice
1   Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, Canada
,
Tilly Ping
1   Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, Canada
,
Dieter Herr
2   Knoll AG, Ludwigshafen, Germany
,
Volker Laux
2   Knoll AG, Ludwigshafen, Germany
› Author Affiliations
Further Information

Publication History

Received 10 April 2000

Accepted after revision 27 July 2000

Publication Date:
08 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Previous studies in rats show that unfractionated heparin and the low molecular weight heparin logiparin have a dose-dependent antithrombotic effect and are found in endothelium and plasma when administered orally. Objectives of the present study were to determine if similar evidence of absorption could be observed with oral reviparin sodium. Thrombosis incidence was determined 4 h after application of 10% formalin in methanol to the exposed jugular vein. A dose-dependent antithrombotic effect was observed when 0.01 to 7.5 mg/kg (20 rats/group) was administered by stomach tube immediately following thrombus initiation. Thrombotic incidence was also significantly reduced when 0.025 mg/kg was given 4 and 2 h prior to, immediately after, and 2 and 3 h following thrombus initiation. Reviparin was recovered from endothelium and plasma in trace amounts at all doses. At 0.025 mg/kg, peak aortic endothelial reviparin concentrations were found at 1 and 2 h and peak plasma anti-Xa activity was detected at 2 h. Trace amounts of plasma TFPI were found only at 8 h after administration. Dose-dependent antithrombotic activity and recovery from endothelium and plasma support the hypothesis that orally administered reviparin sodium is absorbed.

Keywords

Reviparin sodium - thrombosis - oral - rats
 

  • References

  • 1 Emmanuele RM, Fareed J. Effects of molecular weight on the bioavailability of heparin. Thromb Res 1987; 48: 591-6.
    CrossrefPubMedGoogle Scholar
  • 2 DalPozzo A, Acquasaliente M, Geron MR. New heparin complexes active by intestinal absorption. I. Multiple ion pairs with basic organic compounds. Thromb Res 2000; 56: 119-24.
    PubMedGoogle Scholar
  • 3 Jaques LB, Hiebert LM, Wice SM. Evidence from endothelium of gastric absorption of heparin and of dextran sulfates 8000. J Lab Clin Med 1991; 117 (02) 122-30.
    PubMedGoogle Scholar
  • 4 Hiebert LM, Wice SM, McDuffie NM, Jaques LB. The heparin target organ – the endothelium. Studies in a rat model. Quart J Med 1993; 86: 341-8.
    PubMedGoogle Scholar
  • 5 Hiebert LM, Wice SM. Antithrombotic effects of oral heparins in a rat model. Thromb Haemost 1997; Suppl 296-7 (Abstract).
    PubMedGoogle Scholar
  • 6 Hiebert LM, Wice SM, Ping T, Hileman RE, Capila I, Linhardt RJ. Tissue distribution and antithrombotic activity of unlabeled or 14C-labeled porcine intestinal mucosal heparin following administration to rats by the oral route. Can J Physiol Pharm 2000; 78: 307-20.
    CrossrefPubMedGoogle Scholar
  • 7 Hiebert LM, Wice SM, Jaques LB. Antithrombotic activity of oral unfractionated heparin. J Cardiovasc Pharmacol 1996; 28: 26-9.
    CrossrefPubMedGoogle Scholar
  • 8 Blake OR, Ashwin JG, Jaques LB. An assay for the antithrombotic activity of anticoagulants. J Clin Path 1959; 12: 118-22.
    CrossrefPubMedGoogle Scholar
  • 9 Hiebert LM, Jaques LB. The observation of heparin on endothelium after injection. Thromb Res 1976; 8: 195-204.
    CrossrefPubMedGoogle Scholar
  • 10 Jaques LB, Wice SM, Hiebert LM. Determination of absolute amounts of heparin and of dextran sulfate in plasma in microgram quantities. J Lab Clin Med 1990; 115 (04) 422-32.
    PubMedGoogle Scholar
  • 11 Leone-Bay A, Paton DR, Freeman J, Lercara C, O’Toole D, Gschneidner D, Wang E, Harris E, Rosado C, Rivera T, DeVincent A, Tai M, Mercogliano F, Agarwal R, Leipold H, Baughman RA. Synthesis and evaluation of compounds that facilitate the gastrointestinal absorption of heparin. J Med Chem 1998; 41: 1163-71.
    CrossrefPubMedGoogle Scholar
  • 12 Dunn JM, Hollister AS. Oral bioavailability of heparin using a novel delivery system. Curr Ther Res 1995; 56 (08) 738-45.
    CrossrefPubMedGoogle Scholar
  • 13 Baughman RA, Kapoor SC, Agarwal RK, Kisicki J, Catella LF, FitzGerald GA. Oral delivery of anticoagulant doses of heparin. A randomized, double-blind, controlled study in humans. Circulation 1998; 98: 1610-5.
    CrossrefPubMedGoogle Scholar
  • 14 Rivera TM, Leone-Bay A, Paton DR, Leipold HR, Baughman RA. Oral delivery of heparin in combination with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate: pharmacological considerations. Pharm Res 1997; 14: 1830-4.
    CrossrefPubMedGoogle Scholar
  • 15 Ofosu FA. Pharmacological actions of sulodexide. Semin Thromb Hemost 1998; 24 (02) 127-38.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Sue TK, Jaques LB, Yuen E. Effects of acidity, cations and alcoholic fractionation on absorption of heparin from gastrointestinal tract. Can J Physiol Pharmacol 1976; 54: 613-7.
    CrossrefPubMedGoogle Scholar