Dabigatran etixilate and traumatic brain injury: Evolving anticoagulants require evolving care plans

AIM: To investigate the outcomes of trauma patients with traumatic brain injury(TBI) on Dabigatran Etexilate(DE). METHODS: Following IRB approval, all patients taking DE who were admitted to our level 1 trauma service were enrolled in the study. Injury complexity, length of stay(LOS), intensive care length of stay, operative intervention, therapeutic interventions and outcomes were analyzed retrospectively. RESULTS: Twenty-eight of 4310 admissions were taking DE. Eleven patients were excluded on concurrent antiplatelet therapy. Average age was 77.14 years(64-94 years), and average LOS was 4.7 d(1-35 d). Thirty-two percent were admitted with intracranial hemorrhage. Eighteen percent received factor Ⅶ, and 22% received dialysis in attempts to correct coagulopathy. Mortality was 21%.CONCLUSION: The low incidence, absence of reversal agents, and lack of practice guidelines makes managing patients with TBI taking DE frustrating and provider specific. Local practice guidelines may be helpful in managing such patients.

Traumatic fatal cerebral hemorrhage in an old patient with a history of multiple sclerosis under dabigatran： a case report and review of the literature

One disadvantage of direct anticoagulant drug is the lack of an antidote, which may become relevant in patients with traumatic brain in- jury. A 77-years old man with atrial fibrillation and syncope received dabigatran despite recurrent falls. Due to a ground-level-fall, he suffered from subarachnoidal and intraparenchymal hemorrhages, subdural hematoma and brain edema with a midline shift. Despite osteoelast/c trepanation and hematoma-evacuation he remained comatose and died seven days later without regaining consciousness. Most probably, decreased dabigatran clearance due to increased age might have contributed to the fatal course. We suggest withholding anticoagulant therapy in patients with unexplained falls. If anticoagulant therapy is deemed necessary, vitamin-K-antagonists with their potential for laboratory monitoring and reversal of anticoagulant activity should be preferred.

Association between body mass index and the risk of bleeding in elderly patients with non-valvular atrial fibrillation taking dabigatran:a cohort study

Background Uncertainty remains regarding the association between body mass index(BMI)and the risk of bleeding in patients with non-valvular atrial fibrillation(NVAF).We aimed to investigate the association between BMI and the risk of bleeding in elderly NVAF patients taking dabigatran.Methods A total of 509 elderly NVAF patients,who were being treated at twelve centers in China from February 2015 to December 2017 and taking dabigatran,were analyzed.The exposure and outcome variables were BMI at baseline and bleeding events within the subsequent six months,respectively.Cox proportional hazards regression analysis was used to evaluate the association between BMI and the risk of bleeding.Moreover,the Cox proportional hazards regression with cubic spline functions and smooth curve fitting was conducted.Results During the six-month follow-up,50 participants experienced bleeding.Every 1 kg/m^2 increase in BMI was associated with a 12%increased risk of bleeding(P=0.021).Compared to those with BMI values in Tertile 1(<22.5 kg/m^2),the adjusted hazard ratio(HR)of bleeding for participants in Tertile 2(22.5–25.3 kg/m^2)and Tertile 3(>25.3 kg/m^2)were 2.71(95%CI:1.02–7.17)and 3.5(95%CI:1.21–8.70),respectively.The Ptrend-value was significant in all models.The adjusted smooth curve showed a linear association between BMI and bleeding.None of the stratified variables showed significant effect modification on the association between BMI and bleeding(Pinteraction>0.05).Conclusions BMI was significantly and positively associated with the risk of bleeding in elderly NVAF patients treated with dabigatran.

Dabigatran,rivaroxaban,and apixaban are superior to warfarin in Asian patients with non-valvular atrial fibrillation:An updated metaanalysis

BACKGROUND Most of the randomized clinical trials that led to the wide use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation(AF)originated from western countries.AIM To systematically review and quantitatively synthesize the real-world data regarding the efficacy and safety of dabigatran,rivaroxaban,and apixaban compared to warfarin for stroke prevention in Asian patients with non-valvular AF.METHODS Medline,Cochrane,and ClinicalTrial.gov databases were reviewed.A randomeffect model meta-analysis was used and I-square was utilized to assess the heterogeneity.The primary outcome was ischemic stroke.The secondary outcomes were all-cause mortality,major bleeding,intracranial hemorrhage,and gastrointestinal bleeding.RESULTS Twelve studies from East Asia or Southeast Asia and 441450 patients were included.Dabigatran,rivaroxaban,and apixaban were associated with a significant reduction in the incidence of ischemic stroke[hazard ratio(HR)=0.78,95%confidence interval(CI):0.65-0.94;HR=0.79,95%CI:0.74-0.85,HR=0.70,95%CI:0.62-0.78;respectively],all-cause mortality(HR=0.68,95%CI:0.56-0.83;HR=0.66,95%CI:0.52-0.84;HR=0.66,95%CI:0.49-0.90;respectively),and major bleeding(HR=0.61,95%CI:0.54-0.69;HR=0.70,95%CI:0.54-0.90;HR=0.58,95%CI:0.43-0.78;respectively)compared to warfarin.CONCLUSION Dabigatran,rivaroxaban,and apixaban appear to be superior to warfarin in both efficacy and safety in Asians with non-valvular AF.

Dabigatran in cardiovascular disease management:A comprehensive review

Dabigatran,a direct thrombin inhibitor,has robust data for the treatment of deep venous thrombosis and pulmonary embolism,stroke prevention in non-valvular atrial fibrillation,and the prophylaxis of venous thromboembolism(VTE)after knee and hip replacement.Recent studies have evaluated dabigatran to determine its safety and efficacy in such conditions as VTE in malignancy,coronary artery disease,mechanical and bioprosthetic valves,and antiphospholipid syndrome.This article provides a comprehensive review on the role of dabigatran in various cardiovascular diseases.

Dabigatran in the Treatment of Extensive Cerebral Venous Thrombosis:A Case Report

Background: Cerebral venous thrombosis (CVT) is a rare type of cerebrovascular disease associated with a 15% rate of death or function dependence. The mainstay of treatment for CVT is systemic anticoagulation, despite venous hemorrhagic infarction. Vitamin K antagonists have long been the only available option for anticoagulation;however, the past few years have brought the development of many new target-specific drugs, collectively called non-vitamin K antagonist oral anticoagulants (NOACs). Although emerging evidence suggests NOACs have an acceptable safety and tolerability profile in CVT, there are limited data available and no randomized controlled trials have been performed to date. Case Presentation: This describes the case of a patient with CVT occurring during an infection who was successfully treated with a NOAC, dabigatran, after a difficult time on warfarin. Conclusions: A case of extensive and deep CVT was identified. Dabigatran 150 mg treatment twice daily in this patient resulted in no additional damage to the brain. This case study illustrates that the use of NOACs such as dabigatran can be safe and effective in patients with CVT.

Idarucizumab reverses dabigatran-induced anticoagulation in treatment of gastric bleeding:A case report

BACKGROUND The drug instructions for dabigatran recommend adjusting the dosage to 110 mg twice daily for patients with bleeding risk,and performing at least one renal function test per year for patients with moderate renal impairment.However,owing to chronic insidiously worsening renal insufficiency,dabigatran can still accumulate abnormally,necessitating therapy with idarucizumab to reverse the anticoagulation due to severe erosive gastritis with widespread stomach mucosal bleeding.CASE SUMMARY A 76-year-old woman with a history of atrial fibrillation who took dabigatran 110 mg twice daily as directed to lessen the chance of stroke,was transported to the hospital with hematemesis and melena.Laboratory findings revealed severe lifethreatening,blood-loss-induced anemia with a hemoglobin(Hb)level of 41.0 g/L and marked coagulation abnormalities with thrombin time(TT)>180 s,most likely caused by dabigatran-induced metabolic disorder.Aggressive acid suppressive,hemostatic,and blood transfusion therapy resulted in the misconception that the bleeding was controlled,with subsequent rebleeding.Idarucizumab was administered in a timely manner to counteract dabigatran’s anticoagulant impact,and 12 h later,TT was determined to be 17.4 s,which was within the normal range.Finally,the patient had no active bleeding signs and laboratory findings showed an Hb level of 104 g/L and TT of 17.7 s.CONCLUSION Renal function,coagulation function,and dabigatran concentration should be regularly monitored in older patients.Proton pump inhibitor and dabigatran coadministration is still controversial in preventing upper gastrointestinal tract bleeding.

Major bleeding events in octagenarians associated with drug interactions between dabigatran and P-gp inhibitors

Background The direct oral anticoagulant dabigatran does not require any routine therapeutic drug monitoring.Yet,concerns about possible drug interactions susceptible to increase its inherent bleeding risk,especially in very elderly patients,have been raised recently.The aim of our study was to evaluate to what extent the co-prescription of P-gp inhibitors with dabigatran may increase its plasma levels and lead to bleeding complications,in usual conditions of care of the very elderly.Methods Fifty-eight patients over 85 years old with non valvular atrial fibrillation receiving dabigatran were included in a prospective cohort.Prescriptions were screened for the presence of P-gp inhibitors(Group A)or not(Group B).Results Patients from Group A had increased dabigatran mean plasma concentrations as compared with patients from Group B(A vs.B:182.2±147.3 vs.93.7±64.9 ng/m L).One third of the patients from Group A had dabigatran concentrations that were deemed"out of range"versus none in Group B(P=0.05).This was associated with more frequent bleeding complications in Group A(A:30.4%,B:8.6%,P=0.04).Conclusion In our cohort of very elderly patients,at least,the co-prescription of dabigatran with P-gp inhibitors in usual conditions of care resulted in higher dabigatran plasma concentrations and more frequent bleeding occurrences.

QbD Approach Method Development for Estimation of Dabigatran Etexilate along with Its Impurities and Identification of Degradants in Capsule Dosage Form

The concept of Quality by Design was demonstrated in the development of a stability-indicating assay and related substances method by HPLC for Dabigatran Etexilate Capsules dosage form. Method design, method evaluation, method control and life cycle management were explained by systematic flow chart. Analytical Target Product profile was defined. The method was developed using the Inertsil ODS-3V, 150 mm × 4.6 mm, 5 μm column using the gradient program with ammonium formate buffer as mobile phase A and acetonitrile as mobile phase B. Risk assessment was performed as part of method evaluation. Design of experiment tools was used to optimize the chromatographic conditions. A two-level Full Factorial Design along with Face Centered Central Composite design augmentation was employed and statistical analysis of the experimental data uncovered the significant influential of chromatographic factors. The design space and the contour plot suggest that the current center point parameters can be further modified, resulting in better acceptability of the response parameters. The performance of the optimized method was validated according to current ICH guidelines. Dabigatran Etexilate Capsules was subjected to various stress conditions like oxidative, acid, base, hydrolytic, thermal, humidity, and photolytic degradations and evaluated chromatograms at 220 nm. The degradation products were well separated from each other and main peak, demonstrating the stability-indicating power of the method. One of the major degradant impurities, which are forming in neutral hydrolysis stress condition, is isolated and characterized by using analytical techniques like IR, LC-MS and NMR. Degradation pathway for Dabigatran Etexilate was proposed based on forced degradation data along with reaction mechanism.

Safety of Dabigatran in Patients with Non-valvular Atrial Fibrillation： A Short-Term Registry

Dabigatran is a new oral anticoagulant that has been approved by the Food and Drug Administration for the treatment of patients with NVAF （non-valvular atrial fibrillation）. The paper is to retrospectively evaluate the safety of dabigatran in patients with NVAF. We performed a retrospective cohort analysis of our registries for patients using dabigatran. The clinical safety endpoints included major bleeding, stroke, death, and any other reported or documented adverse events. All other major and minor events were recorded and documented during the treatment period. Of the 80 patients included in the analysis, 26% of those receiving a dose of 150 mg experienced adverse events, including two cases of minor bleeding and one case of stroke, whereas 8% of those receiving a dose of 110 mg experienced adverse events, including one case of major gastric bleeding and one case of death. The most common adverse event was gastric distress. Moreover, we noted cases of minor urethral and optic nerve bleeding, major gastric bleeding, stroke, and death. Treatment with dabigatran is primarily successful in low-risk profile patients, without any major or minor events, whereas high-risk patients may require further evaluation before dabigatran treatment initiation and careful monitoring during the treatment period.

Association of ABCB1 gene polymorphisms rs1128503, rs2032582, rs4148738 with anemia in patients receiving dabigatran after total knee arthroplasty

Purpose:Dabigatran is usually prescribed in recommended doses without monitoring of the blood coagulation for the prevention of venous thromboembolism after joint arthroplasty.ABCB1 is a key gene in the metabolism of dabigatran etexilate.Its allele variants are likely to play a pivotal role in the occurrence of hemorrhagic complications.Methods:The prospective study included 127 patients with primary knee osteoarthritis undergoing total knee arthroplasty.Patients with anemia and coagulation disorders,elevated transaminase and creatinine levels as well as already receiving anticoagulant and antiplatelet therapy were excluded from the study.The association of ABCB1 gene polymorphisms rs1128503,rs2032582,rs4148738 with anemia as the outcome of dabigatran therapy was evaluated by single-nucleotide polymorphism analysis with a realtime polymerase chain reaction assay and laboratory blood tests.The beta regression model was used to predict the effect of polymorphisms on the studied laboratory markers.The probability of the type 1 error(p)was less than 0.05 was considered statistically significant.BenjaminiHochberg was used to correct for significance levels in multiple hypothesis tests.All calculations were performed using Rprogramming language v3.6.3.Results:For all polymorphisms there was no association with the level of platelets,protein,creatinine,alanine transaminase,prothrombin,international normalized ratio,activated partial thromboplastin time and fibrinogen.Carriers of rs1128503(TT)had a significant decrease of hematocrit(p=0.001),red blood count and hemoglobin(p=0.015)while receiving dabigatran therapy during the postoperative period compared to the CC,CT.Carriers of rs2032582(TT)had a significant decrease of hematocrit(p=0.001),red blood count and hemoglobin(p=0.006)while receiving dabigatran therapy during the postoperative period compared to the GG,GT phenotypes.These differences were not observed in carriers of rs4148738.Conclusion:It might be necessary to reconsider thromboprophylaxis with dabigatran in carriers of rs1128503(TT)or rs2032582(TT)polymorphisms in favor of other new oral anticoagulants.The longterm implication of these findings would be the reduction of bleeding complications after total joint arthroplasty.

基于《中国医疗机构药品评价与遴选快速指南(第二版)》的口服抗凝药物临床综合评价

目的基于《中国医疗机构药品评价与遴选快速指南(第二版)》,对口服抗凝药物(OACs)进行综合评价,以期为医疗机构药品遴选、临床用药决策提供参考。方法收集评价证据,从临床属性(有效性和安全性)、药学特性、经济性及其他属性4个维度对纳入的药品赋分与评价。结果所有纳入评价的OACs综合评分均在70分以上,华法林综合评分最高。临床属性和药学特性是药品遴选评价的核心属性,当仅评估临床属性和药学特性时,评分最高的药品是艾多沙班。结论OACs是长期抗凝治疗患者的首选药物,不同OACs在临床治疗中有不同的优势。通过《指南(第二版)》对OACs进行遴选评价,可为医疗机构药品遴选与科学、合理、安全用药提供依据。

达比加群酯治疗老年非瓣膜性房颤患者的效果观察

目的探讨达比加群酯治疗老年非瓣膜性房颤患者对凝血功能、心功能的影响及不良反应和预后。方法本研究为随机对照试验,共纳入2020年1月至2023年9月期间天津医科大学第二医院130例老年非瓣膜性房颤患者。通过随机数字表法将患者分为A组(华法林治疗,43例)、B组(利伐沙班治疗,43例)和C组(达比加群酯治疗,44例)。A组男性22例,女性21例,年龄为(74.56±6.43)岁;心功能分级Ⅰ级23例、Ⅱ级20例。B组男性24例,女性19例,年龄为(73.89±6.21)岁;心功能分级Ⅰ级22例、Ⅱ级21例。C组男性20例,女性24例,年龄为(74.12±6.38)岁;心功能分级Ⅰ级23例、Ⅱ级21例。A组接受华法林钠片治疗,每日一次,起始剂量为2.5 mg,后根据国际标准化比值(INR)调整剂量,每次调整0.5mg,保持INR在2.0~3.0之间;B组接受利伐沙班片治疗,每次15mg,每日一次;C组接受达比加群酯胶囊治疗,每次110 mg,每日两次。疗程为2个月。对比3组患者肝肾功能指标[肌酐(Cr)、尿素氮(BUN)、丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)]的水平、凝血功能[凝血酶时间(TT)、纤维蛋白原(FIB)、活化部分凝血活酶时间(APTT)、血浆凝血酶原时间(PT)]、心房颤动栓塞风险CHA2DS2-VASc评分、心房颤动抗凝出血风险HAS-BLED评分和不良反应(皮肤瘀斑、恶心呕吐、脑卒中、血尿)的发生情况,并随访3个月,统计3组的血栓栓塞形成率和出血情况。采用重复测量方差分析、χ^(2)检验、Fisher确切概率法。结果治疗2个月后,B组和C组Cr、BUN、ALT和AST水平低于A组,差异均有统计学意义(均P<0.05)。B组和C组TT、APTT、PT高于A组,FIB低于A组,差异均有统计学意义(均P<0.05)。A组、B组和C组CHA2DS2-VASc和HAS-BLED评分较治疗前略升高,但差异均无统计学意义(均P>0.05)。A组、B组和C组的不良反应发生率为16.28%(7/43)、4.65%(2/43)、2.27%(1/44);C组的不良反应发生率低于A组,差异有统计学意义(P<0.05)。随访3个月后,B组和C组的血栓栓塞形成率和轻微出血率略低于A组,但差异均无统计学意义(均P>0.05)。结论相比华法林,达比加群酯和利伐沙班在治疗老年非瓣膜性房颤患者中能改善肝肾功能和凝血功能,降低不良反应发生率,减少血栓栓塞和出血事件,显示出更好的治疗效果和安全性。

Individualized anti-thrombotic therapy for acute myocardial infarction complicated with left ventricular thrombus: A case report

BACKGROUND Presently,there is no established standard anti-blood clot therapy for patients facing acute myocardial infarction(AMI)complicated by left ventricular thrombus(LVT).While vitamin K antagonists are the preferred choice for oral blood thinning,determining the best course of blood-thinning medication remains challenging.It is unclear if non-vitamin K antagonist oral blood thinners have different effectiveness in treating LVT.This study significantly contributes to the medical community.CASE SUMMARY The blood-thinning treatment of a patient with AMI and LVT was analyzed.Triple blood-thinning therapy included daily enteric-coated aspirin tablets at 0.1 g,daily clopidogrel hydrogen sulfate at 75 mg,and dabigatran etexilate at 110 mg twice daily.After 15 d,the patient’s LVT did not decrease but instead increased.Clinical pharmacists comprehensively analyzed the cases from the perspective of the patient’s disease status and drug interaction.The drug regimen was reformulated for the patient,replacing dabigatran etexilate with warfarin,and was administered for six months.The clinical pharmacist provided the patient with professional and standardized pharmaceutical services.The patient’s condition was discharged after meeting the international normalized ratio value(2-3)criteria.The patient fully complied with the follow-up,and the time in the therapeutic range was 78.57%,with no serious adverse effects during pharmaceutical monitoring.CONCLUSION Warfarin proves to be an effective drug for patients with AMI complicated by LVT,and its blood-thinning course lasts for six months.

新型口服抗凝药dabigatran etexilate

Dabigatran etexilate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。该药在预防静脉血栓栓塞症(venous thromboem bolism,VTE)中已完成Ⅲ期临床试验,治疗急性VTE和心房颤动(atrial fibrillation,AF)的预防正在进行Ⅲ期临床试验。2008年3月,欧盟已批准其在欧盟27个成员国上市。现对其作用机制、药动学、药效学、临床应用及安全性等做一简要介绍。

Determination of dabigatran in dog plasma by LC-MS/MS and its application to a pharmacokinetic study of dabigatran etexilate nanosuspension

In this study, a sensitive and rapid LC-MS/MS method was developed and validated to determine dabigatran in plasma of beagle dogs after oral administration of dabigatran etexilate nanosuspension （DABE-NS）. The analytes （dabigatran） and sertraline hydrochloride （internal standard, IS） were separated on a Kromasil C18 column using gradient elution consisting of methanol and formate buffer at a flow rate of 0.4 mL/min in 20 min. Detection and quantitation were carded out by multiple reaction monitoring following the transitions： m/z 472.17→289.07 and 305.98→275.00 for dabigatran and IS at positive ion mode, respectively. The calibration curves were linear from 1.0 to 500.0 ng/mL for dabigatran with r = 0.9995. The accuracy of each analyte ranged from 94.8% to 107.1%, and the precision was within 6%. Besides, this method was successfully applied in the investigation of the pharmacokinetic profile of dabigatran in beagle dogs after oral administration of DABE-NS. The maximum concentration and the areas under curves of dabigatran for DABE-NS were significantly higher than those of control formulation, indicating improved oral absorption.

达比加群酯-d_(3)的合成

研究抗凝血药物达比加群酯-d_(3)的合成工艺。以4-氯-3-硝基苯甲酸甲酯为起始原料,氘代甲胺盐酸盐为氘代试剂,经氘代甲基化、取代、还原、缩合、环合、水解、亲核等反应得到关键氘化中间体3-{[(2-{[(4-氰基苯基)氨基]甲基}-1-(甲基-d_(3))苯并咪唑-5-基)氧亚基](吡啶-2-基)氨基}丙酸乙酯,而后再经氨解和亲核反应,成功制备稳定的达比加群酯-d_(3),8步反应总产率为6.4%,目标化合物结构经NMR和MS确认,同位素丰度达99.7%。该合成方法原料简单易得、操作简便、重现性好,可用于达比加群酯-d_(3)的合成。

超高龄持续性心房颤动患者心率变异性与基础临床特征的关系分析

目的 探讨超高龄(≥80岁)持续性心房颤动(简称房颤)患者的心率变异性(HRV)与基础临床特征的关系。方法 选取108例超高龄持续性房颤患者纳入房颤组,另选取127例超高龄窦性心律老人纳入对照组,监测24 h动态心电图,比较2组心率、HRV时域指标[正常RR间期标准差(SDNN)、全程每5 min RR间期平均值的标准差(SDANN)、相邻NN间期差值的均方根(RMSSD)、全程记录中5 min NN间期标准差平均值(SDNN index)、心率变异指数(HRV index)和相邻NN间期差值>50 ms的心搏数占NN间期总搏数的百分比(PNN50)]。收集房颤患者的基础临床特征,采用多元线性回归分析探讨HRV时域指标与心率、基础临床特征的相关性。结果 房颤组的SDNN、RMSSD、HRV index、PNN50、SDNN index均高于对照组,差异有统计学意义(P<0.01)。多元线性回归分析结果显示,SDNN升高与高血压(P=0.001)、服用β受体阻滞剂(P=0.003)、心率慢(P<0.001)显著相关,RMSSD升高与高血压(P=0.040)、服用β受体阻滞剂(P=0.002)、心率慢(P<0.001)显著相关,HRV index升高与心力衰竭(P=0.003)、心率慢(P<0.001)显著相关,PNN50升高与心率慢(P=0.004)显著相关;SDNN index升高与服用β受体阻滞剂(P=0.002)、心率慢(P<0.001)显著相关,SDANN升高与高血压(P=0.006)、心率慢(P<0.001)、服用达比加群(P=0.021)显著相关。结论 超高龄持续性房颤患者的HRV与基础临床特征存在相关性,该现象可能源于自主神经系统的活动状态。

达比加群抗凝机理的光谱研究

达比加群酯(DE)是一种新型口服抗凝药,用于预防非瓣膜性房颤患者的卒中和全身性血管栓塞。达比加群酯本身没有药理活性,其活性成分是在血浆和肝脏中经酯酶催化水解生成的达比加群(DAB)。尽管已经被用于临床治疗,活性成分达比加群的极性基团苯甲脒和羧基在其与凝血酶(Thr)结合时的作用机理仍不清晰,并且目前还未找到针对达比加群的特定逆转剂。采用稳态和瞬态荧光光谱、分子对接模拟等方法研究了DAB与凝血酶在模拟生理条件下的相互作用。通过研究极性基团酯化前后DAB与凝血酶作用时的时间分辨荧光光谱,揭示了DAB对凝血酶的荧光猝灭包含动态猝灭和静态猝灭的双重机制,指出DAB苯甲脒基团与凝血酶之间的静电导向效应是DAB与凝血酶快速有效形成复合物的关键动力学因素。运用分子对接模拟方法研究了DAB与凝血酶相互作用时的分子构象,探究DAB极性基团的酯化对两者结合能的影响。通过比较DAB双极性基团酯化后的达比加群酯(DE)、 DAB羧酸基团酯化后的达比加群乙酯(DAE)、以及DAB苯甲醚基团酯化后的达比加群己酯(DAH)与凝血酶相互作用的荧光光谱和分子对接模拟结果,进一步验证了极性基团在DAB与凝血酶结合时的重要作用。获得了DAB和DE与牛血清白蛋白(BSA)在生理pH条件下相互作用的稳态和瞬态荧光光谱的对照结果,提出DAB的极性基团在其与凝血酶的选择性结合中发挥重要作用。研究结果为提高达比加群药物生理活性以及逆转剂的研究提供了理论和实验依据。