Trends in the development of oral anticoagulants

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References

• 1 Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. American College of Chest Physicians. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133, s844–s886 (2008).
  Google Scholar
• 2 Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133, s546–s592 (2008).
  MedlineGoogle Scholar
• 3 Fuster V, Rydén LE, Cannom DS et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 123, e269–e367 (2011).
  MedlineGoogle Scholar
• 4 Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 110, 1042–1046 (2004).
  MedlineGoogle Scholar
• 5 Cohen AT, Tapson VF, Bergmann JF, Goldhaber SZ, Kakkar AK, Deslandes B et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 371, 387–394 (2008).
  MedlineGoogle Scholar
• 6 Gross PL, Weitz JI. New anticoagulants for the treatment of venous thromboembolism. Arterioscler. Thromb. Vasc. Biol. 28, 380–386 (2008).• Comprehensive review on novel anticoagulants.
  Medline CASGoogle Scholar
• 7 Geerts W, Bergquist D, Pineo GF, Heit JA, Samama CM, Lassen MR et al. Prevention of venous thromboembolism. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133, 381S–453S (2008).
  Medline CASGoogle Scholar
• 8 Eikelboom JW, Zelenkofske SL, Rusconi CP. Coagulation Factor IXa as a target for treatment and prophylaxis of venous thromboembolism. Arterioscler. Thromb. Vasc. Biol. 30, 382–387 (2010).
  Medline CASGoogle Scholar
• 9 Mavrakanas T, Bounameaux H. The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism. Pharm. Therap. 130, 46–58 (2011).
  Medline CASGoogle Scholar
• 10 Hirsh J, Raschke R. Heparin and low-molecular-weight heparin. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126, s188–s203 (2004).
  Google Scholar
• 11 Petitou M, Casu B, Lindahl U. 1976–1983, a critical period in the history of heparin: the discovery of the antithrombin binding site. Biochemie 85, 83–89 (2003).• Comprehensive paper on heparin.
  Medline CASGoogle Scholar
• 12 Weitz JI, Eikelboom JW, Samama MM. New antithrombotic drugs. Antithrombotic therapy and prevention of thrombosis, 9th edition. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141, e120S–e151S (2012).
  Medline CASGoogle Scholar
• 13 Bauer KA, Hawkins DW, Peters PC et al. Fondaparinux, a synthetic pentasaccharide: the first in a new class of antithrombotic agents – the selective Factor Xa inhibitors. Cardiovasc. Drug. Rev. 20, 37–52 (2002).• Comprehensive article on fondaparinux.
  Medline CASGoogle Scholar
• 14 Motlekar NA, Youan BB. The quest for non-invasive delivery of bioactive macromolecules: a focus on heparins. J. Control. Release 113, 91–101 (2006).
  Medline CASGoogle Scholar
• 15 Ramadan A, Lagarce F, Tessier-Marteau, Thomas O, Legras P, Macchi L et al. Oral fondaparinux: use of lipid nanocapsules as nanocarriers and in vivo pharmacokinetic study. Int. J. Nanomed. 6, 2941–2951 (2011).• Efficient in vivo formulation of fondaparinux in lipid capsules.
  Medline CASGoogle Scholar
• 16 Jaques LB. Heparins: anionic polyelectrolyte drugs. Pharmacol. Rev. 31, 100–166 (1980).
  Google Scholar
• 17 Samama MM, Gerotziafas GT. Evaluation of the pharmacological properties and clinical results of the synthetic pentasaccharide (fondaparinux). Thromb. Res. 109, 1–11 (2003).
  Medline CASGoogle Scholar
• 18 Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palaretti G. Pharmacology and management of the vitamin K antagonists. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133, s160–s198 (2008).
  Google Scholar
• 19 Bauer KA. Recent progress in anticoagulant therapy: oral direct inhibitors of thrombin and Factor Xa. J. Thromb. Haemost. 9, 12–19 (2011).
  Medline CASGoogle Scholar
• 20 Becattini C, Vedovati MC, Agnelli G. Old and new oral anticoagulants for venous thromboembolism and atrial fibrillation: a review of the literature. Thromb. Res. 129, 392–400 (2012).• Comprehensive review on anticoagulants.
  Medline CASGoogle Scholar
• 21 Mangiafico RA, Mangiafico M. Emerging anticoagulant therapies in atrial fibrillation: new options, new challenges. Curr. Med. Chem. 19, 4688–4698 (2012).
  Medline CASGoogle Scholar
• 22 Miesbach W, Seifried E. New direct oral anticoagulants-current therapeutic options and treatment recommendations for bleeding complications. Thromb. Haemost. 108, 1–7 (2012).
  MedlineGoogle Scholar
• 23 Paliwal R, Paliwal SR, Agrawal GP, Vyas SP. Recent advances in search of oral heparin therapeutics. Med. Res. Rev. 32, 388–409 (2012a).• Comprehensive review on oral administration of heparin.
  Medline CASGoogle Scholar
• 24 Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW. The anticoagulant activation of antithrombin by heparin. Proc. Natl Acad. Sci. USA 94, 14683–14688 (1997).
  Medline CASGoogle Scholar
• 25 Hirsh J. Current anticoagulant therapy – unmet clinical needs. Thromb. Res. 109(Suppl. 1), s1–s8 (2003).
  Medline CASGoogle Scholar
• 26 Perzborn E. Factor Xa inhibitors. New anticoagulants for secondary haemostasis. Hämostaseologie 29, 260–267 (2009).
  Medline CASGoogle Scholar
• 27 Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct Factor Xa inhibitor. Nat. Rev. Drug Disc. 10, 61–75 (2011).
  Medline CASGoogle Scholar
• 28 Kaatz S, Korrides PA, Garcia DA, Spyrolous AC, Crowther M, Douketis JD et al. Guidance on the emergent reversal of oral thrombin and Factor Xa inhibitors. Am. J. Hematol. 87, s141–s145 (2012).
  Medline CASGoogle Scholar
• 29 Roehrig J, Straub A, Pohlmann J, Lampe T, Pernerstorfer J, Schlemmer KH et al. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5yl}methyl) thiophene 2 carboxamide (BAY 59–7939): an oral, direct Factor Xa inhibitor. J. Med. Chem. 48, 5900–5908 (2005).
  Medline CASGoogle Scholar
• 30 Perzborn E, Strassburger A, Wilmen A et al. In vitro and in vivo studies of the novel antithrombotic agent BAY- 59–7939- an oral, direct Factor Xa inhibitor. J. Thromb. Haemost. 3, 514–521 (2005).
  Medline CASGoogle Scholar
• 31 Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59–7939-an oral, direct Factor Xa inhibitor-after multiple dosing in healthy male subjects. Eur. J. Clin. Pharmacol. 61, 873–880 (2005a).
  Medline CASGoogle Scholar
• 32 Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59–7939, an oral, direct Factor Xa inhibitor. Clin. Pharmacol. Ther. 78, 412–421 (2005b).
  Medline CASGoogle Scholar
• 33 Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb. Haemost. 103, 572–585 (2010).
  Medline CASGoogle Scholar
• 34 Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom E, Oldgren J, Parekh A et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 1139–1151 (2009).
  Medline CASGoogle Scholar
• 35 Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J. Thromb. Thromb. 31, 326–343 (2011).
  Medline CASGoogle Scholar
• 36 Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J. Med. Chem. 45, 1757–1766 (2002).
  Medline CASGoogle Scholar
• 37 Wienen W, Stassen JM, Priepke H et al. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb. Haemost. 98, 155–162 (2007).
  Medline CASGoogle Scholar
• 38 Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab. Disp. 36, 386–399 (2008).
  Medline CASGoogle Scholar
• 39 Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br. J. Clin. Pharmacol. 64, 292–303 (2007).
  Medline CASGoogle Scholar
• 40 Ahrens I, Peter K, Lip GY, Bode C. Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Discov. Med. 13, 445–450 (2012).
  MedlineGoogle Scholar
• 41 Holster IL, Valkhoff VE, Kuipers EJ, Tjwa ET. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology 145(1), 105–112 (2013).
  Medline CASGoogle Scholar
• 42 Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J. Am. Coll. Cardiol. 64(11), 1128–1139 (2014).
  Medline CASGoogle Scholar
• 43 Honickel M, Treutler S, van Ryn J, Tillmann S, Rossaint R, Grottke O. Reversal of dabigatran anticoagulation ex vivo: porcine study comparing prothrombin complex concentrates and idarucizumab. Thromb. Haemost. 113(4), (2015).
  MedlineGoogle Scholar
• 44 Lu G, DeGuzman FR, Hollenbach SJ et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation Factor Xa. Nat. Med. 19(4), 446–451 (2013).
  Medline CASGoogle Scholar
• 45 Bianchini EP, Fazavana J, Picard V, Borgel D. Development of a recombinant antithrombin variant as a potent antidote to fondaparinux and other heparin derivatives. Blood 117, 2054–2060 (2011).
  Medline CASGoogle Scholar
• 46 Petitou M, Nancy-Portebois V, Dubreucq G, Motte V, Meuleman D, de Kort M et al. From heparin to EP217609: The long way to a new pentasaccharide-based neutralisable anticoagulant with an unprecedented pharmacological profile. Thromb. Haemost. 102, 804–810 (2009).
  Medline CASGoogle Scholar
• 47 Weitz DS, Weitz JI. Update on heparin: what do we need to know? J. Thromb. Thrombol. 29, 199–207 (2010).
  Medline CASGoogle Scholar
• 48 Chong BH, Isaacs A. Heparin-induced thrombocytopenia: what clinicians need to know. Thromb. Haemost. 101, 279–283 (2009).
  Medline CASGoogle Scholar
• 49 Moazed B, Hiebert LM. Movement of heparins across rat gastric mucosa is dependent on molecular weight and pH. Pharm. Res. 26, 189–195 (2009).
  Medline CASGoogle Scholar
• 50 Goldberg M, Gomez-Orellana I. Challenges for the oral delivery of macromolecules. Nat. Rev. Drug Disc. 2, 289–295 (2003).
  Medline CASGoogle Scholar
• 51 Motlekar NA, Srivenugopal KS, Wachtel MS, Youan BB. Oral delivery of low-molecular-weight heparin using sodium decanoate as absorption enhancer reaches therapeutic levels. J. Drug Target. 13, 573–583 (2005).
  Medline CASGoogle Scholar
• 52 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. 14, 1830–1834 (1997).
  Medline CASGoogle Scholar
• 53 Leone-Bay A, Paton D, Variano B, Leipold H, Rivera T, Miura-Fraboni J et al. Acylated non-α amino acids as novel agents for the oral delivery of heparin sodium. J. Control. Release 50, 41–49 (1998).
  Medline CASGoogle Scholar
• 54 Brayden D, Creed E, O'Connell A, Leipold H, Agarwal R, Leone-Bay A. Heparin absorption across the intestine: effects of sodium N-[8-(2-hydroxybenzoy)amino] caprylate in rat in situ intestinal installations and in caco-2 monolayers. Pharm. Res. 14, 1772–1779 (1997).
  Medline CASGoogle Scholar
• 55 Hull R, Kakkar AK, Marder VJ, Baughman R, Leone-Bay A, Goldberg M. Oral SNAC-heparin vs, enoxaparin for preventing venous-thromboembolism following total hip replacement. Blood 100, 148 (2001).
  Google Scholar
• 56 Pineo G, Hull R, Marder V. Oral delivery of heparin: SNAC and related formulations. Best Pract. Res. Clin. Haematol. 17, 153–160 (2004).
  Medline CASGoogle Scholar
• 57 Arbit E, Goldberg M, Gomez-Orellana I, Majuru S. Oral heparin: status review. Thromb. J. 4, 1–7 (2006).
  MedlineGoogle Scholar
• 58 Baughman RA, Kapoor SC, Agarwal RK et al. Oral delivery of anticoagulant doses of heparin: a randomized, double-blind, controlled study in humans. Circulation 98, 1610–1615 (1998).
  Medline CASGoogle Scholar
• 59 Berkowitz SD, Marder VJ, Kosutic G, Baughman RA. Oral heparin administered with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty. J. Thromb. Haemost. 1, 1914–1919 (2003).
  Medline CASGoogle Scholar
• 60 Leone-Bay A, O'Shaughnessy C, Agarwal R, Rivera-Schaub T, Rosado-Gray C, Gerspach L. Oral low molecular weight absorption from solution and solid dosage form in rat, dog and monkey models. Pharm. Technol. 38–46 (2002).
  Google Scholar
• 61 Thanou M, Verhoef JC, Junginger HE. Oral drug absorption enhancement by chitosan and its derivatives. Adv. Drug Deliv. Rev. 52, 117–126 (2001a).
  Medline CASGoogle Scholar
• 62 Thanou C, Verhoef J, Nihot M, Verheidjen J, Jungiger H. Enhancement of the intestinal absorption of low molecular weight heparin in rats and pigs using carbopol 934P. Pharm. Res. 18, 1638–1641 (2001b).
  Medline CASGoogle Scholar
• 63 Kast CE, Guggi D, Langoth N, Bernkop-Schnürch A. Development and in vivo evaluation of an oral delivery system for low molecular weight heparin based on thiolated polycarbophil. Pharm. Res. 20, 931–936 (2003).
  Medline CASGoogle Scholar
• 64 Clausen AE, Kast CE, Bernkop-Schnürch A. The role of glutathione in the permeation enhancing effect of thiolated polymers. Pharm. Res. 19, 602–608 (2002).
  Medline CASGoogle Scholar
• 65 Hejazi R, Amiji M. Chitosan-based gastrointestinal delivery systems. J. Control. Release 89, 151–165 (2003).
  Medline CASGoogle Scholar
• 66 Chen MC, Wong HS, Lin KJ, Chen HL, Wey SP, Sonaje K et al. The characteristics, biodistribution and bioavailability of a chitosan-based nanoparticulate system for the oral delivery of heparin. Biomaterials 30, 6629–6637 (2009).
  Medline CASGoogle Scholar
• 67 Thanou M, Nihot MT, Jansen M, Verhoef JC, Junginger HE. Mono-N-carboxymethyl chitosan (MCC), a polyampholytic chitosan derivative, enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo. J. Pharm. Sci. 90, 38–46 (2001c).
  Medline CASGoogle Scholar
• 68 Thanou M, Henderson S, Kydonieus A, Elson C. N-sulfonato-N, O-carboxymethylchitosan: a novel polymeric absorption enhancer for the oral delivery of macromolecules. J. Control. Release 117, 171–178 (2007).
  Medline CASGoogle Scholar
• 69 Grabovac V, Schmitz T, Föger F, Berknop-Schnürch A. Papain: an effective permeation enhancer for orally administered low molecular weight heparin. Pharm. Res. 24, 1001–1006 (2007).
  Medline CASGoogle Scholar
• 70 Bock U, Kolac C, Borchard G et al. Transport of proteolytic enzymes across caco-2 cell monolayers. Pharm. Res. 15, 1393–1400 (1998).
  Medline CASGoogle Scholar
• 71 Jiao Y, Ubrich N, Hoffart V et al. Anticoagulant activity of heparin following oral administration of heparin-loaded microparticles in rabbits. J. Pharm. Sci. 91, 760–768 (2002a).
  Medline CASGoogle Scholar
• 72 Jiao Y, Ubrich N, Hoffart V et al. Preparation and characterization of heparin-loaded polymeric microparticles. Drug Dev. Ind. Pharm. 28, 1033–1042 (2002b).
  Medline CASGoogle Scholar
• 73 Jiao Y, Ubrich N, Marchand-Arvier M et al. In vitro and in vivo evaluation of oral heparin–loaded polymeric nanoparticles in rabbits. Circulation 105, 230–235 (2002c).
  Medline CASGoogle Scholar
• 74 Hoffart V, Ubrich N, Lamprecht A et al. Microencapsulation of low molecular weight heparin into polymeric particles designed with biodegradable and nonbiodegradable polycationic polymers. Drug Del. 10, 1–7 (2003).
  Medline CASGoogle Scholar
• 75 Hoffart V, Lamprecht A, Maincent P, Lecompte T, Vigneron C, Ubrich N. Oral bioavailability of a low molecular weight heparin using a polymeric delivery system. J. Control. Release 113, 38–42 (2006).
  Medline CASGoogle Scholar
• 76 Sun W, Mao S, Wang Y et al. Bioadhesion and oral absorption of enoxaparin nanocomplexes. Int. J. Pharm. 386, 275–281 (2010).
  Medline CASGoogle Scholar
• 77 Paliwal R, Paliwal SR, Agrawal GP, Vyas SP. Chitosan nanoconstructs for improved oral delivery of low molecular weight heparin: in vitro and in vivo evaluation. Int. J. Pharm. 422, 179–184 (2012b).
  Medline CASGoogle Scholar
• 78 Hayes PY, Ross BP, Thomas BG, Toth I. Polycationic lipophilic-core dendrons as penetration enhancers for the oral administration of low molecular weight heparin. Bioorg. Med. Chem. 14, 143–152 (2006).
  Medline CASGoogle Scholar
• 79 Lee DY, Lee J, Lee S, Kim SK, Byun Y. Lipophilic complexation of heparin based on bile acid for oral delivery. J. Control. Release 123, 39–45 (2007).
  Medline CASGoogle Scholar
• 80 Scala-Bertola J, Rabiskova M, Lecompte T, Bonneaux F, Maincent P. Granules in the improvement of oral heparin bioavailability. Int. J. Pharm. 374, 12–16 (2009).
  Medline CASGoogle Scholar
• 81 Leonard TW, Lynch J, McKenna MJ, Brayden DJ. Promoting absorption of drugs in humans using medium-chain fatty acid-based solid dosage forms: GIPET™. Exp. Op. Drug Deliv. 3, 685–692 (2006).
  Medline CASGoogle Scholar
• 82 Ito Y, Kusawake T, Rama Prasad YV, Sugioka N, Shibata N, Takada K. Preparation and evaluation of oral solid heparin using emulsifier and adsorbent for in vitro and in vivo studies. Int. J. Pharm. 317, 114–119 (2006).
  Medline CASGoogle Scholar
• 83 Prasad YV, Minamimoto T, Yoshikawa Y et al. In situ intestinal absorption studies on low molecular weight heparin in rats using Labrasol as absorption enhancer. Int. J. Pharm. 271, 225–232 (2004).
  MedlineGoogle Scholar
• 84 Lee YK, Kim SH, Byun Y. Oral delivery of new heparin derivatives in rats. Pharm. Res. 17, 1259–1264 (2000).
  Medline CASGoogle Scholar
• 85 Lee YK, Nam JH, Shin HC, Byun Y. Conjugation of low molecular weight heparin and deoxycholic acid for the development of a new oral anticoagulant agent. Circulation 104, 3116–3120 (2001).
  Medline CASGoogle Scholar
• 86 Lee YK, Kim SK, Lee DY et al. Efficacy of orally active chemical conjugate of low molecular weight heparin and deoxycholic acids in rats, mice and monkeys. J. Control. Release 111, 290–298 (2006).
  Medline CASGoogle Scholar
• 87 Kim SK, Lee EH, Vaishali B, Lee S, Lee YK, Kim CY et al. Tricaprylin microemulsion for oral delivery of low molecular weight heparin conjugates. J. Control. Release 105, 32–42 (2005).
  Medline CASGoogle Scholar
• 88 Kim SK, Vaishali B, Lee E, Lee S, Lee YK, Kumar TS et al. Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation. Thromb. Res. 117, 419–427 (2006).
  Medline CASGoogle Scholar
• 89 Kim SK, Lee DY, Lee E et al. Absorption study of deoxycholic acid-heparin conjugate as a new form of oral-anticoagulant. J. Control Release 120, 4–10 (2007).
  Medline CASGoogle Scholar
• 90 Kim SK, Huh J, Kim SY, Byun Y, Lee DY, Moon HT. Physicochemical conjugation with deoxycholic acid and dimethylsulfoxide for heparin oral delivery. Bioconj. Chem. 22, 1451–1458 (2011).
  Medline CASGoogle Scholar
• 91 van Boeckel CAA, Petitou M. The unique antithrombin III binding domain of heparin: a lead to new synthetic antithrombotics. Angew. Chem. Int. Ed. Engl. 32, 1671–1818 (1993).
  Google Scholar
• 92 Herbert JM, Petitou M, Lormeau JC, Cariou R, Necciari J, Magnani HN et al. SR 90107A/Org 31540, a novel anti-Factor Xa antithrombotic agent. Cardiov. Drugs Rev. 1, 1–26 (1997).
  Google Scholar
• 93 Donat F, Duret JP, Santoni A, Cariou R, Necciari J, Magnani H et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin. Pharmacokinet. 41, 1–9 (2002).
  Medline CASGoogle Scholar
• 94 Cariou R. Le pentasaccharide (fondaparinux sodium, Arixtra^®): avantage à la synthèse. STV 16, 335–338 (2004).
  Google Scholar
• 95 Vetter A, Perera G, Leithner K, Klima G, Berknop-Schnürch A. Development and in vivo bioavailability study of an oral fondaparinux delivery system. Eur. J. Pharm. Sci 41, 489–497 (2010).
  Medline CASGoogle Scholar
• 96 Leonard TW, Coughlan DC, Cullen A. Pharmaceutical compositions of selective Factor Xa inhibitors for oral administration. WO 2011/120033 A1 (2011).
  Google Scholar
• 97 Meissonnier J, Sicre N, Sabate G, Dubreucq G, Nancy-Portebois V, Petitou M. Pharmaceutical oral dosage form containing a synthetic oligosaccharide. WO 2011/073408 A2 (2011).
  Google Scholar
• 98 Ralay-Ranaivo B, Desmaële D, Bianchini EP, Lepeltier E, Bourgaux C, Borgel D et al. Novel self assembling nanoparticles for the oral administration of fondaparinux: synthesis, characterization and in vivo evaluation. J. Control Release 194, 323–331 (2014).• Self-assembling nanoparticles made using bioconjugates of fondaparinux.
  Medline CASGoogle Scholar