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DOI: 10.1055/s-0037-1613092
Absence of Placental Transfer of Pentasaccharide (Fondaparinux, Arixtra®) in the Dually Perfused Human Cotyledon in vitro
Publication History
Received
08 October 2001
Accepted after revision
17 January 2002
Publication Date:
11 December 2017 (online)
Summary
The synthetic pentasaccharide, fondaparinux, is the first of a new antithrombotic class: selective factor Xa inhibitors. Comparative clinical trials of fondaparinux versus heparins in prevention and treatment of venous thromboembolism are ongoing. Little is known about fondaparinux during pregnancy, as women of child-bearing potential were excluded from clinical trials. No particular safety issue, for either mother or fetus, has been reported for heparins. The objective of this study was to compare in vitro the steady state placental transfer of fondaparinux and enoxaparin at the plasma concentrations reached during acute treatment of venous thromboembolism (1.75 µg/mL and 1 anti- Xa IU/mL respectively), using antipyrine (20 mg/L) as reference. No biological activity was detectable in the fetal venous effluent during perfusion of enoxaparin-antipyrine, fondaparinux-antipyrine or control media. Furthermore, fetal venous samples did not differ significantly from fetal arterial samples. This apparent absence of placental transfer supports further evaluation of fondaparinux in pregnant women.
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References
- 1 Duplaga BA, Rivers CW, Nutescu E. Dosing and monitoring of low-molecular-weight heparins in special populations. Pharmacotherapy 2001; 21: 218-34.
- 2 Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 2001; 119: 122S-31S.
- 3 Olson ST, Björk I, Sheffer R, Craig PA, Shore JD, Choay J. Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions: resolution of the antithrombin conformational change contribution to heparin rate enhancement. J Biol Chem 1992; 267: 12528-38.
- 4 Rosenberg RD. Redesigning heparin. N Engl J Med 2001; 344: 673-5.
- 5 Turpie AGG, Gallus AS, Hoek JA. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001; 344: 619-25.
- 6 Weitz JI, Hirsh J. New anticoagulant drugs. Chest 2001; 119: 95S-107S.
- 7 Boneu B, Necciari J, Cariou R, Sié P, Gabaig AM, Kieffer G, Dickinson J, Lamond G, Moelker H, Mant T, Magnani H. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/ORG31540) with high affinity to antithrombin III in man. Thromb Haemost 1995; 74: 1468-73.
- 8 Lassen MR, Bauer KA, Eriksson BI. et al. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in elective hip replacement surgery. A randomized double-blind comparison. Lancet. In press.
- 9 Turpie AGG, Bauer KA, Eriksson BI. et al. A randomized double-blind comparison of fondaparinux with enoxaparin for the prevention of venous thromboembolism after elective hip replacement surgery. Lancet. In press.
- 10 Eriksson BI, Bauer KA, Lassen MR. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298-304.
- 11 Bauer KA, Eriksson BI, Lassen MR. et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-10.
- 12 Panigel M, Pascaud M, Brun JL. Une nouvelle technique de perfusion de l’espace intervilleux dans le placenta isolé. Pathol Biol 1967; 114: 822-8.
- 13 Schneider H, Panigel M, Dancis J. Transfer across the perfused human placenta of antipyrine, sodium and leucine. Am J Obstet Gynecol 1972; 13: 40-7.
- 14 Bourget P, Roulot C, Fernandez H. Models for placental transfer studies of drugs. Clin Pharmacokinet 1995; 28: 161-80.
- 15 Dimitrakakis C, Papageorgiou P, Papageorgiou I, Antzaklis A, Sakarelou N, Michalas S. Absence of transplacental passage of the low molecular weight heparin enoxaparin. Haemostasis 2000; 30: 243-8.
- 16 Lagrange F, Péhourcq F, Bannwarth B, Leng JJ, Saux MC. Passage of S(+)-and R(−)-ketoprofen across the human isolated perfused placenta. Fundam Clin Pharmacol 1998; 12: 286-91.
- 17 Lagrange FJ, Brun JL, Clot PF, Leng JJ, Saux MC, Kieffer G, Bannwarth BG. Placental transfer of SR49059 in the human dually perfused cotyledon in vitro. Placenta 2001; 22: 870-5.
- 18 Paolucci F, Clavies MC, Nadal T, Perez Y, Donat F, Necciari J. Rapid and sensitive chromogenic assay to determine pentasaccharide in human plasma and urine: application to a pharmacokinetic study. (Submitted).
- 19 Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne-Pardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, Mac MRGillavry, Hamulyak K, Theunissen IM, Hunt BJ, Buller HR. Safety of low-molecular-weight-heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-72.
- 20 Lepercq J, Conard J, Borel-Derlon A, Darmon JY, Boudignat O, Francoual C, Priollet P, Cohen C, Yvelin N, Schved JF, Tournaire M, Borg JY. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. Br J Obstet Gynecol 2001; 108: 1134-40.
- 21 Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 687-93.
- 22 Casele HL, Laifer SA, Woelkers DA, Venkataramanan R. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol 1999; 181: 1113-7.