Improved anticoagulant effect of fucosylated chondroitin sulfate orally administered as gastroresistant tablets

Abstract

Fucosylated chondroitin sulfate (FucCS) is a potent anticoagulant polysaccharide extracted from sea cucumber. Its anticoagulant activity is attributed to the presence of unique branches of sulfated fucose. Although this glycosaminoglycan exerts an antithrombotic effect following oral administration, high doses are necessary to achieve the maximum effect. The diminished activity of FucCS following oral administration is likely due to its degradation in the gastrointestinal tract and its limited ability to cross the intestinal cell membranes. The latter aspect is particularly difficult to overcome. However, gastro-resistant tablet formulation may help limit the degradation of FucCS in the gastrointestinal tract. In the present work, we found that the oral administration of FucCS as gastro-resistant tablets produces a more potent and prolonged anticoagulant effect compared with its administration as an aqueous solution, with no significant changes in the bleeding tendency or arterial blood pressure. Experiments using animal models of arterial thrombosis initiated by endothelial injury demonstrated that FucCS delivered as gastro-protective tablets produced a potent antithrombotic effect, whereas its aqueous solution was ineffective. However, there was no significant difference between the effects of FucCS delivered as gastro-resistant tablets or as aqueous solution in a venous thrombosis model, likely due to the high dose of thromboplastin used. New oral anticoagulants tested in these experimental models for comparison showed significantly increased bleeding tendencies. Our study provides a framework for developing effective oral anticoagulants based on sulfated polysaccharides from marine organisms. The present results suggest that FucCS is a promising oral anticoagulant.

Precise Structure and Anticoagulant Activity of Fucosylated Glycosaminoglycan from Apostichopus japonicus: Analysis of Its Depolymerized Fragments

“…The lack of consensus on the structure of AjFG is mainly due to the limitations of the present techniques and strategies. In order to obtain FG fragments for structural analysis, partial acid hydrolysis was used to degrade FG, but it resulted in the loss of FucS sidechains and sulfate groups [17,18]. Hydrogen peroxide depolymerization was another method for FG degradation, but its exact cleavage position in polysaccharide chain remains unclear to date.…”

Anticoagulant and Antithrombotic Properties of Three Structurally Correlated Sea Urchin Sulfated Glycans and Their Low-Molecular-Weight Derivatives

“…A recent work describing the comparative effects of a sea urchin sulfated fucan and a sea cucumber FCS, both structurally containing 2,4-disulfated fucose units either as composing units of the backbone (former) or as lateral branching residues (latter), has reinforced the role of the 2,4-disulfated fucose motifs in coagulation and thrombosis [ 19 ]. Direct oral administration of FCS [ 20 ], or administration via gastro-resistant tablets [ 21 ], has also been recently proposed to improve the delivery, bioavailability and pharmacological function of the holothurian GAG [ 20 , 21 ].…”

Semisynthetic Isomers of Fucosylated Chondroitin Sulfate Polysaccharides with Fucosyl Branches at a Non-Natural Site

“… 3 Furthermore, fCS retains its activity even with an oral administration, because it is digested neither in the gastric tract nor by intestinal bacterial enzymes. 4 The possibility of an oral delivery and to exploit an alternative mechanism of actions are key aspects in the research for new anticoagulants drugs. For these reasons fCS stands as a promising anticoagulant drug candidate for heparin replacement.…”