高抗血栓活性的低分子肝素

LOW MOLECULAR WEIGHT HEPARIN OF HIGH ANTITHROMBOTIC ACTIVITY

以生产肝素的副产品──低抗凝活性肝素为原料，采用亚硝酸控制解聚法制得低分子肝素（ＬＭＷＨ）；在固定ｐＨ值和亚硝酸用量的条件下，探明ＬＭＷＨ分子量与反应温度和时间呈反变。测定了产物的理化常数，抗凝效价和抗ＦＸａ活性。以大鼠颈动脉血栓模型研究证明分子量为５３００ｄ的产物具有较强的抗栓活性；此外对琼脂所致大鼠足跖肿胀、棉球所致小鼠炎症性肉芽肿组织增生都具有显著抑制作用。以抗ＦＸａ活性为检测指标，研究了家兔一次静脉注射的药物动力学，结果显示ＬＭＷＨ的生物半衰期ｔ（１／２）约为肝素的３倍，全身清除率Ｃｌｓ比肝素小，血药－时曲线下面积ＡＵＣ和表观分布容积Ｖ比肝素大。以对家兔实验性血栓形成的影响为药效学指标，确定了ＬＭＷＨ口服胶囊的配方组成及其对家兔血液流变学及实验性血栓形成的影响。

A low molecular weight heparin (LMWH) was prepared from low anticoagulant activity heparin (LAAH),a side product accompanying commercial heparin, by depolymerization with nitrous acid. With pH value and content of nitrous acid fixed,the molecular weight of LMWH showed an inverse change between reaction temperature and time.The physical and chemical parameters, anticoagulant activity and anti-FXa activity of the product were determined. The LMWH with molecular weight 5300d possessed the strongest antithrombotic activity evaluated by the thrombus model in common carotid artery of rats.The LMWH could significantly inhibit agar-induced paw edema in rats and cotton-ball-induced inflammatory granulation tissue hyperplasia in mice.With anti-FXa activity as index,the pharmacokinetics of LMWH was studied in rabbits after a single iv injection, which showed that the biological half-life of LMWH was almost three times as long as that of heparin, the systematic clearance of LMWH was slower,the AUC and V of LMWH were bigger. With the effect on experimental thrombus formation as the pharmacodynamics index, the formulation and effects of LMWH oral capsules composed of oleic acid and bovine bile salt upon rabbit hemorheology and thrombus formation were studied.