达比加群酯抗凝作用特异性逆转药物——idarucizumab

新型口服抗凝药可用于心房颤动患者的卒中预防和静脉血栓栓塞性疾病的治疗。与维生素K拮抗剂相比,新型口服抗凝药的相关出血事件较少,但当出血发生时,医生评估和管理新型口服抗凝药相关性出血的能力仍值得关注。简介依达赛珠单抗、andexanet alfa、ciraparantag、凝血酶原复合物、活化凝血酶原复合物和重组因子Ⅶa等用于止血或逆转新型口服抗凝药抗凝作用的药物研究进展,以期为新型口服抗凝药的临床应用及相关出血事件的处理提供参考。

     

达比加群酯抗凝治疗合理性和安全性评价

目的：调查住院患者接受达比加群酯治疗情况,了解该药的应用现状和不良反应并分析其危险因素,为临床更好的使用达比加群酯提供参考依据。方法：收集中日友好医院2017年4月1日至2018年3月31日住院期间使用达比加群的患者信息,进行回顾性分析。通过分析患者适应证、肝肾情况、凝血指标、不良反应、药物转换及合并用药情况,评价达比加群酯使用的合理性和安全性。结果：共收集患者247例,其中男139例（56.28%）,女108例（43.72%）。年龄29~91岁,平均（72.11±29.26）岁。使用达比加群的患者中老年人有207例（83.80%）,因房颤及房扑入院的患者有184例（74.49%）,占比最大。患者因CrCL<30 mL·min^-1禁忌使用达比加群的情况下仍使用的有10例（4.05%）。19例（7.69%）患者住院期间使用达比加群出现不良反应,出血有14例（73.68%）。服用达比加群期间进行药物转换的患者32例（12.96%）。由华法林向达比加群转换22例（68.75%）,使用错误率为36.36%。由达比加群向华法林转换6例（18.75%）,使用错误率为100%。合用药物中联合使用抗血小板药37例（14.98%）,联合使用胺碘酮16例（6.48%）,临床使用期间应该加强监测。结论：达比加群临床常用于老年非瓣膜性房颤患者,使用前应注意肝肾功能监测,常见不良反应为出血,合并使用抗血小板药和胺碘酮时多注意监护。达比加群与华法林药物转换时错误较多,是药学监护的重点。     

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。     

达比加群酯不良反应文献的分析

通过检索PubMed、中国知网数据库和维普数据库关于达比加群酯不良反应的文献并对其进行回顾性分析和总结。达比加群酯致ADR的个案报道共73例;其性别分布男性44例（60.3%）,女性29例（39.7%）;年龄分布以70岁以上较多（59例,80.8%）;多发生在用药后6个月内（60例,82.2%）;达比加群酯致ADR临床表现以消化系统损害（50.7%）、血液系统损害（15.1%）和心血管系统损害（11.0%）多见。临床使用达比加群酯过程中应重点考量患者肾功能、年龄、体重和性别等危险因素,并重点监测和防治其ADR,避免ADR的发生。     

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)。     

达比加群酯致吞咽困难1例

<正>达比加群酯(dabigatran etexilate)获得美国食品和药物管理局(FDA)批准用于预防非瓣膜性房颤患者卒中和全身性栓塞,是一种直接凝血酶抑制剂,口服经胃肠道吸收后迅速在肝及血浆中被酯酶水解释放出达比加群,后者选择性、可逆性地结合于凝血酶的纤维蛋白特异结合位点,阻止纤维蛋白原裂解为纤维蛋白,同时抑制凝血酶,阻止其介导的血小板活化、聚集和血栓形成,从而发挥     

达比加群酯用于非瓣膜性房颤抗凝治疗的不良反应分析

目的:了解我院达比加群酯致药品不良反应发生的规律和特点,为临床安全合理使用达比加群酯提供参考依据.方法:采用回顾性分析方法,对我院2015年2月-2019年12月上报国家ADR监测中心的19例达比加群酯ADR报告进行统计分析.结果:19例达比加群酯ADR报告中,男女比例为1:1.7;61～70岁患者最多(42.11％)...     

达比加群酯的合成

4-甲胺基-3-硝基苯甲酸(2)经酰氯化后和3-(吡啶-2-基氨基)丙酸乙酯缩合,得3-[(4-甲胺基-3-硝基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,再在Fe-Al-Cu复合催化剂作用下经水合肼还原、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33.6％(以2计).     

达比加群酯降解杂质的合成

目的 为了更好的控制甲磺酸达比加群酯的质量,合成达比加群酯的5个降解杂质。方法 以N-[2-[[(4-氰基苯基)氨基]甲基]-1甲基-1H-5-苯并咪唑]羰基]-N-2-吡啶基-β-氨基丙酸乙酯为原料,经过成脒反应、酰胺反应、水解反应制备了杂质A~E。结果 所得产物经¹H-NMR,LC-MS和¹³C-NMR初步确证了结构,收率≥65%。结论 该合成路线反应条件温和,产品纯度高。     

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。     

Changing anticoagulant paradigms for atrial fibrillation: dabigatran, apixaban and rivaroxaban

INTRODUCTION: Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF. AREAS COVERED: The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug. EXPERT OPINION: Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs.     

Changing anticoagulant paradigms for atrial fibrillation: dabigatran,apixaban and rivaroxaban

Introduction: Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF.

Areas covered: The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug.

Expert opinion: Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs.     

A new approach with anticoagulant development: tailoring anticoagulant therapy with dabigatran etexilate according to patient risk

INTRODUCTION: Although vulnerable patients, including the elderly and those with renal impairment or low body weight, are at greater risk of bleeding and/or venous thromboembolism following total hip or total knee replacement, there have been few clinical studies to determine the optimal dose of anticoagulants for this group. AREAS COVERED: For this paper the authors searched the literature for data on efficacy and bleeding rates with low-molecular-weight heparins and fondaparinux in routine clinical practice; and on the effects of standard or reduced dosing with these anticoagulants or with the oral direct thrombin inhibitor dabigatran etexilate in vulnerable patient groups. EXPERT OPINION: Tailoring anticoagulation therapy according to the risk of individual patients is the best way to optimize the benefit/risk of thrombosis and bleeding, and is recommended on treatment guidelines. Specific recommendations for dose reduction have been made for fondaparinux in renal impairment. The availability of two approved doses of dabigatran etexilate for thromboprophylaxis following orthopedic surgery allows the dose to be tailored to the individual patient's characteristics, based on the age and renal function of the patient, as recommended by the European Medicines Agency, in order to maintain efficacy while decreasing bleeding risk.     

A new approach with anticoagulant development: tailoring anticoagulant therapy with dabigatran etexilate according to patient risk

Introduction: Although vulnerable patients, including the elderly and those with renal impairment or low body weight, are at greater risk of bleeding and/or venous thromboembolism following total hip or total knee replacement, there have been few clinical studies to determine the optimal dose of anticoagulants for this group.

Areas covered: For this paper the authors searched the literature for data on efficacy and bleeding rates with low-molecular-weight heparins and fondaparinux in routine clinical practice; and on the effects of standard or reduced dosing with these anticoagulants or with the oral direct thrombin inhibitor dabigatran etexilate in vulnerable patient groups.

Expert opinion: Tailoring anticoagulation therapy according to the risk of individual patients is the best way to optimize the benefit/risk of thrombosis and bleeding, and is recommended on treatment guidelines. Specific recommendations for dose reduction have been made for fondaparinux in renal impairment. The availability of two approved doses of dabigatran etexilate for thromboprophylaxis following orthopedic surgery allows the dose to be tailored to the individual patient's characteristics, based on the age and renal function of the patient, as recommended by the European Medicines Agency, in order to maintain efficacy while decreasing bleeding risk.     

新型口服抗凝药达比加群酯治疗老年非瓣膜性房颤患者的疗效和安全性研究

目的分析探讨新型口服抗凝药达比加群酯治疗老年非瓣膜性房颤的临床疗效和安全性。方法随机从我院2016年5月～2017年10月收治的老年非瓣膜性房颤患者中抽取80例进行分析,依据其治疗方式分组,其中40例接受华法林治疗(对照组),另40例接受达比加群酯治疗(研究组),观察比较治疗状况。结果研究组出血率为2.50%、卒中率为2.50%、血栓栓塞率为2.50%低于对照组的20.00%、17.50%、17.50%,差异有统计学意义(P 0.05)。研究组不良反应总发生率为5.00%低于对照组27.50%,差异有统计学意义(P 0.05)。治疗前凝血指标组间比较,差异无统计学意义(P 0.05),治疗后,研究组PLT、FIB、PT、抗凝血酶Ⅲ高于对照组,INR低于对照组,差异有统计学意义(P 0.05),APTT比较,差异无统计学意义(P 0.05)。结论分析后得知,新型口服抗凝药达比加群酯治疗老年非瓣膜性房颤,其疗效与华法林一致,但安全性更高,值得推广。     

新型抗凝药达比加群酯对高龄持续性房颤导管射频消融术围术期的抗凝疗效及安全性评价

目的观察新型抗凝药达比加群酯对高龄持续性心房颤动患者导管射频消融术(RFCA)围术期的抗凝疗效,并进行安全性评价。方法选取2012年7月至2014年7月期间收治的高龄(≥75岁)持续性房颤患者84例,所有患者均拟行RFCA。采用随机数字表法将患者分为华法林组和达比加群酯组,均n=42。华法林组术前给予法华林(2.5 mg,qd)治疗1个月,术中给予低分子肝素钠(100 U·kg-1)治疗,术后继续给予法华林(2.5 mg,bid)治疗3个月。达比加群酯组给予达比加群酯(55 mg,bid)治疗1个月,术中给予低分子肝素钠治疗,术后继续给予达比加群酯治疗3个月。比较观察两组患者凝血功能和并发症。结果与治疗前相比,治疗1个月和术后3个月两组患者的凝血功能包括凝血酶原时间(PT)、活化的部分凝血活酶时间(APTT)、凝血酶时间(TT)、国际标准化比值(INR)比较均显著升高(P<0.05),且术后3个月各指标改变更显著(P<0.05);达比加群酯组的APTT、TT和INR显著高于华法林组(P<0.05)。华法林组术中及术后并发症均高于达比加群酯组(P<0.05)。结论达比加群酯在高龄持续性房颤患者RFCA围手术期的抗凝疗效好,能增强抗凝血功能,降低术中和术后并发症发生率。     

Tetronic acids with direct anticoagulant effects

Tetronic Acids with in vitro Anticoagulant Effects Several tetronic acids are synthesized which inhibit, in vitro, the clotting of human blood plasma induced by thromboplastin or actin. In two cases the coagulation induced by thrombin is also inhibited. One tetronic acid shortens the thrombin time by more than 30% thus demonstrating a procoagulant effect.