Fonseca Roberto J C, Sucupira Isabela D, Oliveira Stephan Nicollas M C G, Santos Gustavo R C, Mourão Paulo A S
Roberto J. C. Fonseca, Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho, Caixa Postal 68041, Rio de Janeiro, RJ, Brazil, Tel./Fax: +55 21 2562 2091, E-mail:
Thromb Haemost. 2017 Apr 3;117(4):662-670. doi: 10.1160/TH16-09-0694. Epub 2017 Jan 19.
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.
岩藻糖基化硫酸软骨素（FucCS）是一种从海参中提取的强效抗凝血多糖。其抗凝血活性归因于硫酸化岩藻糖独特分支的存在。尽管这种糖胺聚糖口服后具有抗血栓形成作用，但需要高剂量才能达到最大效果。口服后FucCS活性降低可能是由于其在胃肠道中降解以及穿越肠细胞膜的能力有限。后一个方面尤其难以克服。然而，胃内滞留型片剂剂型可能有助于限制FucCS在胃肠道中的降解。在本研究中，我们发现与以水溶液形式给药相比，以胃内滞留型片剂形式口服FucCS可产生更强效和更持久的抗凝血作用，且出血倾向或动脉血压无显著变化。使用内皮损伤引发的动脉血栓形成动物模型进行的实验表明，以胃保护型片剂形式给药的FucCS产生了强效的抗血栓形成作用，而其水溶液则无效。然而，在静脉血栓形成模型中，以胃内滞留型片剂或水溶液形式给药的FucCS的效果之间没有显著差异，这可能是由于所使用的凝血酶原剂量较高。在这些实验模型中进行比较测试的新型口服抗凝剂显示出血倾向显著增加。我们的研究为基于海洋生物硫酸化多糖开发有效的口服抗凝剂提供了框架。目前的结果表明FucCS是一种有前景的口服抗凝剂。
