Fareed J, Jeske W, Eschenfelder V, Iqbal O, Hoppensteadt D, Ahsan A
Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA.
Thromb Res. 1996;81(2 Suppl):S1-27. doi: 10.1016/0049-3848(95)00226-x.
Some major developments in the area of antithrombotic therapy have occurred during the past decade. Of these, the concept of fractionation of heparin has resulted in the development of several products from this agent. The introduction of low molecular weight heparins (LMWHs) has added a new chapter to the prophylactic and therapeutic management of thromboembolic disorders. These agents are now globally accepted as drugs of choice for post-surgical prophylaxis of deep vein thrombosis (DVT). Currently, the LMWHs are being developed for various therapeutic and cardiovascular indications. Reviparin is an optimized LMWH prepared by controlled nitrous acid digestion of porcine mucosal heparin. This drug has been developed using validated procedures and exhibits a relatively narrow molecular weight distribution in contrast to most other commercially available LMWHs. The specific activity in anticoagulant assays is approximately 32 U/mg whereas the specific activity in terms of anti-Xa units is 120 anti-Xa U/mg. Reviparin is capable of producing a dose- and time-dependent antithrombotic effect in animal models of thrombosis. While the ex vivo effects initially occur at dosages that are antithrombotic, this agent has been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. This agent has also been found to release tissue factor pathway inhibitor (TFPI) after both intravenous and subcutaneous administration. Repeated administration of reviparin produces progressively stronger antithrombotic effects. The current studies are designed to provide additional data on its molecular profile using new calibration methods and additional results on the pharmacological studies in a dose-dependent manner. In particular, the release of TFPI following i.v. and s.c. administration in a primate model is described. The effect of repeated administration mimicking the post-surgical prophylaxis of DVT is also reported in terms of any increase in the antithrombotic or haemorrhagic effects of this agent. Comparative antithrombotic and pharmacological studies are also reported to compare the pharmacological profiles of reviparin, nadroparin and enoxaparin.
在过去十年中，抗血栓治疗领域取得了一些重大进展。其中，肝素的分级分离概念促使了几种基于该药物的产品问世。低分子量肝素（LMWHs）的引入为血栓栓塞性疾病的预防和治疗管理增添了新的篇章。这些药物现已在全球范围内被公认为外科手术后预防深静脉血栓形成（DVT）的首选药物。目前，低分子量肝素正被开发用于各种治疗和心血管适应症。瑞肝素是一种经过优化的低分子量肝素，通过对猪黏膜肝素进行可控的亚硝酸消化制备而成。该药物采用经过验证的程序开发，与大多数其他市售低分子量肝素相比，其分子量分布相对较窄。抗凝测定中的比活性约为32 U/mg，而抗Xa单位的比活性为120抗Xa U/mg。瑞肝素能够在血栓形成的动物模型中产生剂量和时间依赖性的抗血栓作用。虽然体外效应最初在具有抗血栓作用的剂量下出现，但已发现该药物能产生持续的抗血栓作用，且无任何可检测到的体外抗凝作用。还发现该药物在静脉内和皮下给药后均能释放组织因子途径抑制剂（TFPI）。重复给药瑞肝素会产生逐渐增强的抗血栓作用。当前的研究旨在使用新的校准方法提供有关其分子特征的更多数据，并以剂量依赖性方式提供药理学研究的更多结果。特别是，描述了在灵长类动物模型中静脉内和皮下给药后TFPI的释放情况。还报告了模拟DVT外科手术后预防的重复给药效果，涉及该药物抗血栓或出血作用的任何增加。还报告了比较抗血栓和药理学研究，以比较瑞肝素、那屈肝素和依诺肝素的药理学特征。
