新型口服抗凝血药物达比加群酯

全球首个口服凝血酶抑制剂达比加群酯于2008年上市,用于预防人工关节置换术后并发深静脉血栓形成和肺动脉栓塞.该药的成功上市,为人工关节置换术后患者带来了福音.本文将详细介绍其作用机制及临床研究进展.     

新型口服抗凝药达比加群酯

达比加群酯是一种新型口服抗凝药物,通过直接抑制凝血酶起到抗凝作用。达比加群酯2010年10月19日获准在美国上市,是继华法林之后50年来首个在美上市的口服抗凝血新药。该药具有口服、强效、无需特殊用药监测、药物相互作用少、不良反应小等优点。     

HPLC测定达比加群酯中的有关物质

目的 建立达比加群酯原料药中有关物质的测定方法。方法 采用Agilent SB-C₁₈色谱柱(250 mm×4.6 mm,5 μm),以乙腈(A)-0.2%的醋酸铵(B,用冰醋酸调节pH值至4.4)为流动相进行梯度洗脱：0~18 min,90%→40%B;18~30 min,40%B。流速为1.0 mL·min^-1,检测波长为340 nm。结果 各杂质与主峰之间的分离度良好。5个已知杂质：杂质A浓度在0.117 0~1.872 μg·mL^-1内与峰面积呈良好的线性关系,r为0.999 7;杂质B浓度在0.126 5~2.024 μg·mL^-1内与峰面积呈良好的线性关系,r为0.999 5;杂质C浓度在0.113 0~1.808 μg·mL^-1内与峰面积呈良好的线性关系,r为0.999 5;杂质D浓度在0.120 5~1.928 μg·mL^-1内与峰面积呈良好的线性关系,r为0.999 9;杂质E浓度在0.123 0~1.968 μg·mL^-1内与峰面积呈良好的线性关系,r为0.999 6;杂质A、杂质B、杂质C、杂质D和杂质E加样回收率的平均值分别为98.75%,98.91%,98.39%,99.0%和99.73%;RSD分别为0.91%,1.09%,1.22%,1.35%和1.18%。结论 本方法简便、准确可靠,适用于达比加群酯中有关物质的控制。     

新型口服抗凝血剂达比加群酯的研究进展

华法林是大多数国家长期抗凝的主要药物之一。华法林虽然可以口服给药,但其治疗范围狭窄,必须严格掌握治疗指征。此外华法林与其他药物相互作用大,个体差异较大,治疗期间需严密观察病情,并依据国际标准化比率随时调整用量。在近几年中许多新的抗凝血剂已经开发出来。达比加群酯是一种新型口服的直接凝血酶抑制剂。本研究综述了达比加群酯的临床研究进展及潜在适应证,为该药物的临床应用提供依据。     

高龄肾功能异常房颤患者应用达比加群酯病例分享

90岁房颤患者1例,坚持应用达比加群酯0.11 g每日1次治疗,合并基础疾病较多,伴肾功能异常,入院后头部磁共振示左颞叶后部微出血灶可能性大。患者CHA_2DS_2-VASc评分7分,HAS-BLED评分4分,有抗凝治疗适应证,同时出血高危。SAMe-TT_2R_2积分4分,更适合应用新型口服抗凝药。因此临床选择达比加群酯治疗。患者90岁,肾功能异常,为保证临床安全未按指南推荐应用达比加群酯每日0.22 g的剂量,而是选择应用较小剂量。     

逆转达比加群酯抗凝活性的研究进展和处理建议

达比加群酯是一种直接抑制凝血酶的新型口服抗凝药,具有较好的抗凝疗效和安全性,出血是其最常见的不良反应,发生率略低于或类似于华法林和依诺肝素。当服用达比加群酯的患者发生大出血,或者需进行手术或侵入性处理时,常须紧急逆转其抗凝活性。目前尚未研发出达比加群酯特异性解药,临床上应根据患者的出血部位和严重程度,进行综合治疗。监测凝血酶凝固时间（TT）和蛇静脉酶凝结时间（ECT）等指标有助于判断逆转达比加群酯活性的疗效。     

达比加群酯的合成

2-氯吡啶经氧化、亲核取代、Pd/C催化氢化得3-(吡啶-2-基氨基)丙酸乙酯(2).另用对氯甲苯经氧化、硝化、胺化、酰氯化制得4-甲胺基-3-硝基苯甲酰氯(3).2和3缩合得3-[(4-甲胺基-3-硝基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯(4),再经催化氢化还原、酰胺化后闭环、成脒及酰化反应等制得抗凝血药达比加群酯,总收率约12%(以对氯甲苯计).     

达比加群酯的合成

4-甲胺基-3-硝基苯甲酸与3-(吡啶-2-基氨基)丙酸乙酯在羰基二咪唑的作用下反应形成3-[(4-甲胺基-3-硝基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,经锌粉还原得到3-[(3-氨基-4-甲胺基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,随后与N-(4-氰基苯基)甘氨酸在羰基二咪唑以及醋酸作用下一锅制得3-[[2-[(4-氰基苯胺基)甲基]-1-甲基-1H-苯并咪唑-5-羰基](吡啶-2-基)氨基]丙酸乙酯,再进行成脒化反应以及酰化反应后即可制得达比加群酯,总收率约48％.     

比较达比加群酯和华法林用于房颤患者导管消融围手术期的临床效果

目的:对比达比加群酯和华法林在房颤患者导管消融围手术期的应用价值.方法:选取180例在我院行导管消融术治疗的房颤患者,随机分为两组,对照组行华法林治疗,共90例,观察组行加达比群酯治疗,共90例,对比效果.结果:观察组与对照组血栓栓塞事件发生率分别为2.2％、3.3％,组间比较差异不显著,无统计学意义(P>0.05);观察组与对照组出血并发症发生率分别为6.6％、8.8％,组间比较差异不显著,无统计学意义(P>0.05);两组均无严重出血事件发生.结论:对于房颤导管消融围手术期实施达比加群酯治疗可取得与华法林相似的抗凝效果,疗效显著,值得在临床上推广.     

达比加群酯对1例肺栓塞患者凝血功能的影响

目的 探讨达比加群酯对凝血功能的影响及抗凝活性监测的意义。方法 临床药师根据1例肺栓塞患者服用达比加群酯的凝血指标,提出合理的药物治疗建议。结果 患者部分凝血活酶时间（activated partial thromboplastin time,APTT）延长超过正常上限（upper limit of normal,ULN）₂倍,临床药师建议服药后12 h重新检验APTT,目标值为1.5倍ULN,患者复查后达标。结论 特殊人群常规凝血指标监测有助于明确抗凝疗效,采血时机非常关键。APTT可供定性评估,但结果解读需谨慎。     

New therapeutic option for thromboembolism – dabigatran etexilate

Background: Thrombin plays a key role in blood coagulation and haemostasis; thus its inhibition has been identified as a reasonable target to block the coagulation cascade. Direct thrombin inhibitors are potential prophylactic agents for venous thromboembolism and arterial thrombosis, which often accompany operative procedures and cardiac disease, especially orthopedic surgery and atrial fibrillation, respectively. New orally available anticoagulant agents with a wide therapeutic window are keenly anticipated because warfarin and heparins have some disadvantages, and recent progress in pharmaceutical techniques has led to the development of orally administered direct thrombin inhibitors. Objectives: In this review, we discuss the usefulness of dabigatran etexilate as a new therapeutic option for preventing thromboembolism, including chemistry, pharmacokinetics, and pharmacodynamics, from the results of recent clinical studies. Methods: We systematically focused on relevant published studies, as data from recent clinical studies were difficult to obtain owing to their ongoing status. Conclusions: Dabigatran etexilate is a promising new oral anticoagulant that offers greatly expanded therapeutic options for both patients and physicians.     

The evolving role of dabigatran etexilate in clinical practice

Introduction: Stroke and venous thromboembolism (VTE) affect millions of patients. The vitamin K antagonist, warfarin, has been the main oral anticoagulant used to treat these conditions despite many limitations associated with its use. Recently, multiple novel oral anticoagulants have been approved and are reshaping how patients with atrial fibrillation (AF) at risk of stroke and patients with VTE are treated. The direct thrombin inhibitor, dabigatran etexilate, is among these novel agents that have been developed to overcome limitations with warfarin.

Areas covered: In this article, authors describe the pharmacokinetic and pharmacodynamic properties of dabigatran etexilate and summarize the clinical evidence and controversy surrounding its use in the US, Canada and Europe.

Expert opinion: Dabigatran has demonstrated similar efficacy and safety to enoxaparin for VTE prevention in patients undergoing hip and knee arthroplasty, and to warfarin for the treatment of VTE. Dabigatran (110 mg) is noninferior and dabigatran (150 mg) is superior to warfarin for stroke prevention in patients with nonvalvular AF, with a lower rate of intracranial hemorrhage reported at both doses. Apixaban, rivaroxaban and edoxaban provide alternate anticoagulant options to dabigatran. While there are many similarities, there are also significant differences to consider in agent selection based on patient-specific characteristics.     

甲磺酸达比加群酯的合成

目的:研究和改进甲磺酸达比加群酯的合成工艺。方法:以4-甲氨基-3-硝基苯甲酸(2)和3-(吡啶-2-基氨基)丙酸乙酯(3)为原料,经酰氯化、酰胺化、中和成盐和还原制得重要中间体3-[[3-氨基-4-(甲氨基)苯甲酰基](吡啶-2-基)氨基]丙酸乙酯(5)。5再与N-(4-氰基苯基)甘氨酸经酰胺化、闭环、中和成盐、成脒、酰化,进而与甲磺酸成盐制得甲磺酸达比加群酯。结果:中间体及目标化合物经质谱、核磁共振谱、红外光谱等确证,整个工艺的总收率为33.9%。结论:本路线操作简便、成本较低、条件温和、步骤少,适合工业化生产。     

达比加群酯的合成工艺改进

目的 改进达比加群酯的合成工艺,提高反应收率并简化操作。方法 以4-甲胺基-3-硝基苯甲酸为原料,与3-（吡啶-2-基氨基）丙酸乙酯缩合后,经催化氢化、酰胺化后闭环、成脒、与氯甲酸正己酯反应得到达比加群酯。结果与结论 目标化合物的结构经核磁共振氢谱、质谱确证。改进后的合成方法与原工艺相比,环境友好,收率提高了16.4%,总收率为33.75%(以4-甲胺基-3-硝基苯甲酸计)。     

达比加群酯盐的降解产物研究

目的研究6种达比加群酯盐在不同条件下的降解产物,寻找不同酸根与达比加群酯盐稳定性之间的相互关系。方法将6种盐在高温、高湿和光照条件下分别放置10 d后,利用HPLC和LC-MS法对不同盐的降解产物进行深入分析。结果通过LC-MS法解析得到达比加群酯盐的3种关键降解产物,初步推断出不同杂质的产生与所选用的酸根结构密切相关。结论为了寻找更加稳定的达比加群酯盐,需要选用氧化还原性弱,结构中含氧基团少及p Ka值较低的酸根。     

达比加群酯的合成工艺研究

目的 对达比加群酯的合成工艺进行研究。方法 以3-[[[2-[[(4-氰基苯基)氨基]甲基]-1-甲基-1H-苯并咪唑-5-基]羰基](吡啶-2-基)氨基]丙酸乙酯为起始原料,经改进后的Pinner反应得到脒,再与氯甲酸正己酯反应得到达比加群酯。结果 合成了目标化合物,并利用MS和1H-NMR确证了结构;收率为38.8%,质量分数为99.6%。结论 该合成工艺简化了操作,设计合理,终产物达比加群酯收率及纯度较高,具备工业化可行性。     

The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects

AIMS: The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. METHODS: Dabigatran etexilate or placebo was administered orally at single doses of 10-400 mg (n = 40) or at multiple doses of 50-400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. RESULTS: Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8-10 h and 14-17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (V(z)/F) of 1860 l (range 1430-2400 l) and the apparent total clearance after oral administration (CL(tot)/F) of 2031 ml min(-1) (range 1480-2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration-time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups. CONCLUSIONS: These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted.     

达比加群酯相关肾损伤的定性系统评价

目的：探讨达比加群酯相关肾损伤的临床特点及其防治,为安全用药提供参考。方法：检索PubMed、Ovid、Web of Science、Embase、Springer-link、Wiley Oline Library、CNKI、万方数据库和维普数据库,收集达比加群酯相关肾损伤的文献,检索时限均为建库截至2019年1月,提取相关数据进行分析。结果：初筛相关文献156篇,最终纳入符合标准的文献14篇,均来自国外期刊。14篇文献包括达比加群酯相关肾损伤患者14例,其中男9例,女5例;年龄59~89岁,中位年龄为80岁;临床表现主要为出血,其中以血尿为主;在达比加群酯相关肾损伤治疗后,4例肾功能恢复,4例肾功能改善,3例肾功能未恢复,3例肾功能恶化。结论：达比加群酯可能导致肾损伤,在肾损伤相关疾病的基础上也可能导致达比加群酯毒性增加,在出现危及生命的出血的紧急情况下血液透析不一定能达到很好疗效,可使用达比加群酯逆转剂——依达赛珠单抗（idarucizumab）解毒。临床在使用时,应权衡药物使用的利弊,以及时应对不良反应的防治、发生及处理。