抗凝血的低分子量肽类似物

抗凝血药是一类通过影响凝血过程不同环节,阻止血液凝固的药物,主要用于血栓栓塞性疾病的预防与治疗.低分子量肽类似物对天然蛋白酶的酶解稳定性更好,拥有更高的生物活性,易被人体所吸收,是目前抗凝血药物研究中的热点.该文对抗凝血低分子量肽类似物的最新进展予以评述,着重介绍其活性、机理及临床研究进展.     

蜱源抗凝血因子研究进展

蜱是一种人畜共患体表寄生虫,通过叮咬宿主和吸血,将病原体传播给宿主,引发多种疾病。凝血反应是人和动物的重要生理过程,是生理性止血的重要环节。蜱叮咬和吸食宿主血液周期长,在吸血过程中分泌多种抗凝物质,抑制凝血反应,可帮助蜱长时间保持吸血状态。目前,已知的蜱源抗凝物质依据其功能主要包括蛋白酶抑制剂、纤维蛋白(原)溶解剂、血小板聚集抑制剂和血管活性蛋白4大类。这些抗凝血物质可分别作用于凝血级联反应中内源性通路、外源性通路、共同通路中的关键步骤,以及促进纤蛋白溶解和抑制血小板激活,从而抑制宿主血管中的凝血反应。蛋白酶抑制剂主要通过抑制凝血级联反应共同通路中凝血酶和Xa因子活性;纤维蛋白(原)溶解剂引起纤维蛋白原的水解并延迟纤维蛋白凝块的形成;血小板聚集抑制剂通过降解血小板聚集激动剂,并结合血栓素A2(thromboxane A2, TXA2)和血小板上的αIIbβ3整合素抑制血小板聚集;血管活性蛋白抑制宿主血管收缩以及伤口愈合和血管生成。此外,还有一些蜱分泌的其他蛋白分子可通过不同的通路来实现抗凝血作用。本文对迄今为止各类蜱中发现的具有抗凝血活性的蛋白和小分子及其抗凝血作用机制进行总结阐述,将...     

抗凝血蛋白的抗凝溶栓机制

自然界中存在着大量具有抗凝溶栓活性的生物大分子,如水蛭素、蚓激酶等。这些生物大分子主要是通过抑制凝血酶及凝血因子活性,水解纤维蛋白或纤溶酶原,或是抑制血小板聚集来达到抗凝溶栓的作用。该文对这些活性物质的抗凝溶栓机制进行综述。     

国内抗凝血、抗血栓多糖的药理研究进展

目前已经发现许多多糖具有生物活性。综述了国内在多糖的抗凝血、抗血栓药理研究方面的近况。     

凝血因子药物市场分析

凝血因子是一类特殊的药物,是血友病等血液疾病的治疗药物,目前已经成为血液制品的重要组成部分。国外已经有二十多种重组凝血因子药物上市,2015年全球重组凝血因子药物的市场规模已经达到78.54亿美元,未来还将持续增长,Baxalta公司的重组凝血因子产品销售额位居全球首位,达到28.40亿美元。国外有多种重组凝血因子处于研发阶段,其中长效重组凝血因子将成为新的市场增长点。国内各类凝血因子药物的批签发状况良好,且随着国家发展和改革委员会取消血液制品最高零售价,各类产品价格均有不同幅度增长,其中人纤原蛋白原增长幅度最高,达到189%。国产凝血因子市场空间巨大,但存在产品供给和研发力度不足等问题,发展受到限制,必须改革行业管理制度、提高血浆分离技术、加强重组产品研发。     

抗血栓药物的研究进展

血栓栓塞性疾病是引起人类疾病死亡的主要原因之一,随着人们对其发病机制研究与认识的不断深入以及药物设计和筛选技术的日臻成熟,针对各种靶点的新型抗血栓药物不断涌现,如二磷酸腺苷受体阻滞剂、Ⅹ a 因子抑制剂、凝血酶抑制剂等,我国药学研究者也在这些靶向抗血栓药物研究领域取得一定进展。综述我国学者近些年在国内外学术期刊上发表的相关研究论文中所涉及的各类新型抗血小板药物、抗凝血药物和血栓溶解剂的结构、活性和构效关系。     

硇洲马尾藻(S.naozhouense)褐藻多酚的抗凝血活性研究

本文采用溶剂萃取法提取硇洲马尾藻(S.naozhouense)褐藻多酚,并通过超滤进行分子量分级得NW1和NW2两部分,检测其总多酚的含量.通过体内和体外实验检测NW1和NW2体内对凝血时间(CT)、出血时间(BT)、凝血酶原时间(PT)和血浆凝血酶时间(TT)的影响.结果表明,硇洲马尾藻多酚NW1在10～40 mg/kg.d剂量范围能显著延长CT和BT,在5～15 mg/mL浓度范围显著增加PT和TT,表现出良好的全面抗凝血活性;NW2能显著延长CT和BT,对TT有一定的延长作用,但对PT无效果,且在高浓度(15 mg/mL)时表现出显著的缩短PT作用.     

新型锌多糖抗凝血涂层修饰聚氯乙烯导管

目的：提高体外循环聚氯乙烯导管的血液相容性。方法：采用层层自组装的方法在PVC表面形成锌离子和多糖（肝素或硫酸葡聚糖）的复合涂层来提高PVC的血液相容性。结果：傅立叶红外光谱表明锌多糖复合物成功的沉积到PVC管表面,与未修饰的PVC管相比,修饰后的PVC管具有较长的部分活化的凝血酶原时间和很少数量的血小板黏附。体系中引入硫酸葡聚糖后,表面涂层具有更好的稳定性。结论：锌多糖抗凝血涂层很好的提高了聚氯乙烯导管的血液相容性。     

氨酰tRNA 合成酶抑制剂作为新型抗感染药物的研究进展

细菌耐药性的不断上升对现有阶段的抗生素类药物提出了一个严峻的挑战,同时也掀起了针对于新靶标的抗菌药物的研究。氨酰tRNA合成酶(aaRS)催化特定氨基酸连接到相应的tRNA分子上,在蛋白质的合成过程中起着必不可少的作用。氨酰tRNA合成酶的抑制会导致蛋白质合成的停止,扰乱细菌和真菌的生长,因此氨酰tRNA合成酶是一类潜在的抗感染靶标。本文分别综述了天然产物及其衍生的aaRS抑制剂,底物和反应中间体模拟物,通过合成和通过虚拟筛选得到的aaRS抑制剂作为新型抗细菌和抗真菌药物的研究进展,并对aaRS的靶标特点、分类和催化机制作一简要介绍。     

介入诊疗聚氨酯（PU）导管的抗凝血研究进展

扼要概述了介入诊疗聚氨酯（PU）导管的凝血过程，影响因素，改善PU导管材料抗凝血性的途径以及导管用材料抗凝血性能的表征。     

Interaction of alpha 2-macroglobulin-bound thrombin with hirudin

The human thrombin bound to alpha 2-macroglobulin (alpha 2 M) in a 1:1 stoichiometry is still able to interact with one of its specific inhibitors, hirudin. The dissociation constant of the complex hirudin--alpha 2M-bound thrombin is 1 X 10(-7) M, whatever the mode of thrombin binding, covalent or non-covalent.     

Orally efficacious thrombin inhibitors with cyanofluorophenylacetamide as the P2 motif

2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (K_i = 1.2 nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration.     

Antithrombotic effects of LB30870, a potent,orally active,selective and direct thrombin inhibitor,and pharmacokinetics of its prodrug

Antithrombotic activity and bleeding complication of a new potent, selective, and direct thrombin inhibitor, LB30870, were evaluated in comparison with other anticoagulants. In order to improve oral absorption of LB30870, pharmacokinetics of LB30889, which is a double prodrug with blocking groups in both amidine and carboxyl groups, was studied in rats and dogs. LB30870 was more potent than melagatran or argatroban with thrombin inhibition constants of 0.02, 1.3 and 4.5 nM, respectively. All three direct thrombin inhibitors were selective towards other serine proteases with selectivity ratio greater than 1000, except for trypsin. Thrombin binding kinetics of LB30870 showed rapid association and slow dissociation rate constants, demonstrating its potential as anticoagulant. LB30870 was more effective than melagatran or argatroban in plasma clot-bound thrombin inhibition. In the rat venous stasis model of the caval vein, LB30870 reduced wet clot weights in a dose dependent manner after the intravenous bolus with infusion administration. The ED₅₀ of LB30870, melagatran and enoxaparin were 50 μg/kg + 2 μg/kg/min, 35 μg/kg + 1.4 μg/kg/min and 200 μg/kg + 8.3 μg/kg/min, respectively. No significant bleeding problem was observed with LB30870 at the dose up to two times ED₈₀ in rats. LB30889, a double prodrug of LB30870, showed species difference in pharmacokinetics. Its oral bioavailability in rats or dogs was not better than that of LB30870. In conclusion, LB30870 has the potential to be useful as an effective oral anticoagulant for the prevention and treatment of thromboembolic diseases.     

Design,Synthesis and Biological Actmty of Novel Rigid Amidino-Phenylalanine Derivatives as Inhibitors of Thrombin

Abstract

(3S)-(Naphthalene-2-sulfonylamino)-1-[2R-(4-amidinophenyl)-1-piperidinocarbonylethyl]-2-pyrroli-dinone (1a) is a potent inhibitor of thrombin with an IC₅₀ value by 112 times lower than that of NAPAF’ (racemate). The selectivity versus trypsin can be improved by incorporation of substituents on the naphthyl ring. The mode of binding of the compound was determined by X-ray crystallography.     

非胰岛素类糖尿病治疗新药研究进展

糖尿病是一种以高血糖为特征的慢性代谢性疾病,随着生活水平的提高,其发病率逐年上升,已成为危害人类健康的重要因素之 一。对于糖尿病的治疗药物研究,也从对传统机制的药物研究过渡到对具有新靶点和新作用机制的药物研究。其中基于这些新靶点设计 的新型非胰岛素类糖尿病治疗药物已进入临床研究阶段或已上市,给糖尿病的治疗带来了新的思路。按作用靶点和机制分类对较有开发 前景的非胰岛素类糖尿病治疗新药的研究进展进行综述。     

Anticoagulant effects of a Cannabis extract in an obese rat model

Blood coagulation studies were conducted to determine the possible anti-/prothrombotic effect of an organic cannabis extract and the three major cannabinoids, THC, CBD and CBN. The in vitro effect of the cannabis extract on thrombin activity produced an IC50 value of 9.89 mg/ml, compared to THC at 1.79 mg/ml. It was also found that the extract, THC and CBN showed considerable inhibition of thrombin-induced clot formation in vitro with IC50 values of 600, 87 and 83 microg/ml for the extract, THC and CBN respectively. In an in vivo model used to determine clotting times of lean and obese rats treated with a cannabis extract, 50% clotting times were found to be 1.5 and 2 fold greater than their respective control groups, supporting the results obtained in the in vitro model. The study thus shows that Cannabis sativa and the cannabinoids, THC and CBN, display anticoagulant activity and may be useful in the treatment of diseases such as type 2 diabetes in which a hypercoagulable state exists.     

Design, synthesis and SAR of a series of 1,3,5-trisubstituted benzenes as thrombin inhibitors

A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5-trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency.     

Novel anticoagulant polyethylenimine: inhibition of thrombin-catalyzed fibrin formation

Hypercoagulability is often associated with a variety of disease states, leading to cardiovascular complications. Polyethylenimine (PEI) prolonged prothrombin time, demonstrating its anticoagulant potential. In vitro, PEI at low concentration (nM) significantly blocked thrombin-catalyzed fibrin formation, accounting for its mode of anticoagulation. The uncompetitive inhibition by PEI of fibrin formation was independent of the concentration of fibrinogen (FBG), thrombin, or NaCl. PEI showed no effect on thrombin amidolytic activity, suggesting that the blockade of thrombin interaction with FBG could account for the inhibition on fibrin formation. PEI drastically depressed rabbit brain thromboplastin procoagulation monitored by a single-stage clotting assay using human plasma. In a THP-1 monocytic hypercoagulation model, a 4-h exposure to bacterial endotoxin or Ca(2+) ionophore A23187, respectively, resulted in a 5- or 10-fold enhancement in monocytic tissue factor (mTF) procoagulation. mTF hypercoagulation was offset by PEI included in the assay mixture. PEI showed the potential to arrest mTF hypercoagulation with IC(50) around 1.2 nM. Using a chromogenic assay to dissect the extrinsic pathway, we further assessed whether PEI has any effect on other clotting factors. PEI was not an inhibitor for either FVIIa or FXa, having no effect on not only the amidolytic but also their corresponding functionally catalytic activities. Although PEI upregulated TF-dependent FVII activation under the low-salt condition, the effective downstream inhibition of fibrin formation readily abolished and overrode the upstream enhancement, demonstrating the overall anticoagulation. PEI could present a new class of anticoagulant.     

Inhibition of thrombin by synthetic hirudin peptides

To investigate the role of different regions of hirudin in the interaction with the proteinase thrombin, segments of hirudin containing 15-51 residues were synthesized. The C-terminal segment 40-65 inhibited the fibrinogen clotting activity of thrombin but not amidolysis of tosyl-Gly-Pro-Arg-p-nitroanilide. Central peptide 15–42 was insoluble at pH 7, but peptide 15-65 inhibited fibrinogen clotting and amidolysis to an equal extent. The N-terminal loop peptide 1-15 had no inhibitory activity and did not affect the potency of peptide 15-65. These data suggest that the central region inhibits catalysis.     

关节置换术后抗凝药物预防深静脉血栓及相关并发症的临床研究进展

抗凝药物有助于预防全髋关节置换术和全膝关节置换术后深静脉血栓形成,临床上最常使用的传统抗凝药物如低分子肝素、华法林等可以起到很好的预防效果。目前有一类新的口服抗凝药物已经用于临床,为关节置换术后患者带来了一种更方便、安全和有效预防血栓的治疗选择。本篇综述主要针对传统抗凝药物低分子肝素及维生素K拮抗剂,直接凝血酶抑制剂达比加群,以及选择性Xa因子抑制剂利伐沙班和阿哌沙班,对迄今为止传统抗凝药物在全髋关节置换术和全膝关节置换术患者中的临床使用经验、优缺点、以及新型口服抗凝药物最新临床用药进展进行综述,为关节置换术后患者预防深静脉血栓提供用药参考。