口服抗血凝药物研究进展

抗血凝药物通过影响血凝级联反应阻止血液凝集,临床上主要用于预防血栓形成高危人群发展血栓栓塞相关疾病、特别是预防经历主要整形术后患者的静脉血栓栓塞事件以及减少心房纤维性颤动患者的中风风险。抗血凝药物50多年来一直主要由华法林和肝素类物质组成,但华法林存在严重、甚或致死性的出血风险,同时药动学性质的个体差异很大并易受到食物的影响、药物-药物相互作用又十分复杂,实际中难以正确或适宜剂量用药,须频繁进行凝血功能监测;肝素类物质则因需注射给药,故常被限用于住院患者或短期预防静脉血栓栓塞。因此,临床需要有新的更安全、且用药更简便的口服抗血凝药物。现在临床开发中的口服抗血凝药物主要包括直接凝血酶抑制剂、Ⅹa因子抑制剂、Ⅸ因子抑制剂、组织因子抑制剂和新型维生素K拮抗剂等。其中口服直接凝血酶抑制剂达比加群酯和口服Ⅹa因子抑制剂列伐沙班已经大型随机、双盲、对照临床试验证实,它们能够替代华法林成为预防非瓣膜性心房纤维性颤动患者中风和全身栓塞及替代依诺肝素钠成为预防主要整形术后患者静脉血栓栓塞事件的首选用药,具有使此两治疗领域发生巨大变革的深厚潜力。

血凝试验检测结果质量的影响因素及质量改善对策研究

血凝试验检测的质量受到多种因素的影响,通过本文对主要影响因素进行分析,并且针对得出的统计学数据,对质量改善工作的方向进行阐述。方法:本次研究一共选取了200例血凝试验的结果,对结果的影响因素进行具体分析,从工作的各个环节当中查找影响质量的因素,主要包括:患者的用药情况/血凝试验的具体工作环节等,整理可能导致检测结果出现不准确的影响因素,针对具体的情况提出针对性质量控制措施。结果:血凝试验的准确性与患者的用药情况相关,抗血凝药物的协同作用会影响检测结果,试验时用到的材料的保质期长短以及操作人员使用物品的合理性均为影响因素。结论:血凝试验检测质量的影响因素较为复杂,总体而言,患者用药的因素以及材料的保质期对于检测结果的影响较大,应重点注意。

Study on Antithrombotic and Antiplatelet Activities of Low Molecular Weight Fucoidan from Laminaria japonica

The antithrombotic and antiplatelet effects of two fucoidan fractions with low molecular weight and different sulfate content from Laminaria japonica were compared in order to examine the influence of chemical character on their antithrombotic activity and the possible mechanism. Both LMW fucoidan fractions exhibited favorable antithrombotic activity in an Fecl3-induced arterial thrombosis. The antithrombotic activity of LMW fucoidan was related with decrease of TXB2 and whole blood viscosity and hematocrit. LMW fucoidan showed a correlation between anticoagulant, antiaggregant and antithrombotic effects in vivo. For LMW fucoidan, antithrombotic activity required high dose of 5-10 nmol kg-1, concomitantly with increase in anticoagulant activity and inhibition of platelet aggregation. Administration of LMW fucoidan significantly promoted the 6-keto-PGF1α content and decreased the TXB2 content, indicating its inhibition of tissue factor pathway and regulation of metabolism of arachidonic acid. By comparison, highly sulfated fucoidan LF2 with Mw 3900 seemed to be a more suitable choice for antithrombotic drug for its antithrombotic activity accompanied with specific inhibitory activity on platelet aggregation, low anticoagulant activity and low hemorrhagic risk in vivo.

Comparative study between rivaroxaban and conventional low molecular weight heparin anticoagulant in preventing thrombosis

After entering 2010, as main varieties patents of the global non-peptide angiotensin II receptor antagonists （ARB） expire, strong growth of anti-hypertensive drug market will tend to slow down. In drugs acting on the cardiovascular and blood system, antithrombotie drugs will become a new attraction on the market. Antithrombotic drugs are primarily formed by the anti-platelet aggregation, coagulation system activation of plasminogen thrombolytic drugs and the like. Antiplatelet drugs have both prevention and treatment effect, are the main category of antithrombotic drugs. According to IMS Health data, in 2008, sale of anti-thrombosis drug in global market is 180 million U.S. dollars, an increase of 16 %, while in 2009 the growth rate is only 7.95%, reaching $ 19.5 billion, growth rate of antithrombotic drugs is 7.13% in the world＇ s major pharmaceutical market.

Changes of proteins induced by anticoagulants can be more sensitively detected in urine than in plasma

The most fundamental property of biomarkers is change.But changes are hard to maintain in plasma since it is strictly controlled by homeostatic mechanisms of the body.There is no homeostatic mechanism for urine.Besides,urine is partly a filtration of blood,and systematic information can be reflected in urine.We hypothesize that change of blood can be reflected in urine more sensitively.Here we introduce the interference into the blood by two anticoagulants heparin or argatroban.Plasma and urine proteins were profiled by LC-MS/MS and then validated by Western blot in totally six SD female rats before and after the drug treatments.In argatroban treated group,with exactly the same experimental procedure and the same cutoff value for both plasma and urine proteins,62 proteins changed in urine,only one of which changed in plasma.In heparin treated group,27 proteins changed in urine but only three other proteins changed in plasma.Both LC-MS/MS and Western blot analyses demonstrated drug-induced increases in transferrin and hemopexin levels in urine but not in plasma.Our data indicates that urine may serve as a source for more sensitive detection of protein biomarkers than plasma.

Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors

As a coagulation factor in the intrinsic coagulation pathway,factor XIa(FXIa)is an effective and safe target for the development of antithrombotic drugs.Many small-molecule FXIa inhibitors have been discovered,some of which are being evaluated in clinical trials.However,none of them have been approved.In the present study,a highly selective potent FXIa inhibitor with poor solubility reported in our previous work was selected as a lead compound to be further modified to improve FXIa potency and physicochemical properties.The structure-based drug design and structure-activity relationship study led to the discovery of LY8,LY17,and LY25,which demonstrated enhanced FXIa potency and maintained excellent selectivity.In addition,LY8 exhibited significantly improved aqueous solubility,suggesting that it could be a promising compound to be further evaluated.