凝血酶抑制剂比伐卢定的临床应用

比伐卢定是2000年被FDA批准上市的抗凝血药物,它通过直接抑制凝血酶发挥抗凝作用,已被批准应用于PCI／PTCA、HIT／HITTS、ACS等领域。现有研究表明比伐卢定在临床抗凝治疗中有较好的安全性,可以用于常规治疗方案（肝素与糖蛋白IIb／IIIa抑制剂）的替代治疗,而且可以降低出血风险和死亡率。本文主要介绍凝血酶直接抑制剂比伐卢定的药理作用及临床研究,总结分析其安全性及经济效益,并且结合国内临床应用情况,分析其在国内的临床运用前景。     

比伐卢定抗凝作用的研究进展

FDA在2000年批准了一种新的直接凝血酶抑制剂比伐卢定应用于临床，该药是水蛭素的类似物，它通过抑制凝血酶的活性位点而起效。国外将其与其他常用的抗凝药进行了比较研究，认为比伐卢定可以作为普通肝素和血小板糖蛋白Ⅱb／Ⅲa拮抗剂的替代药物应用于非高危患者的经皮冠脉介入治疗。     

比伐卢定在健康人体内的药动学和药效学

目的:研究国产注射用比伐卢定在中国健康受试者体内药动学、药效学特点。方法:将48名健康受试者随机分组,分别接受单次静脉推注0.5,0.75,1.05,0.75 mg.kg-1静脉推注后续以1.75 mg.kg-1.h-1匀速静脉滴注4 h(序贯给药)。给药前后不同时间点取血测定比伐卢定的血药浓度、活化凝血时间(ACT)、凝血酶原活动度(PA)、凝血酶原时间(PT)、部分凝血酶原时间(APTT)和纤维蛋白原(FIB)。采用HPLC-MS-MS法测定受试者血浆样品中比伐卢定的浓度。ACT、PA、PT、APTT和FIB为临床检验所得。结果:(1)注射用比伐卢定在0.5～1.05 mg.kg-1的剂量范围内,呈线性药动学特征;序贯给药在健康受试者体内不存在蓄积。(2)单次静脉推注0.5,0.75,1.05 mg.kg-1比伐卢定后,ACTmax分别为(149.3±26.4)s、(180.7±21.8)s和(197.3±20.7)s,与给药剂量和Cmax进行回归分析,并对回归系数t检验,表明ACTmax与给药剂量和Cmax呈线性相关特征(P<0.05);各剂量组药效达峰时间ACT-tmax与血药浓度达峰时间tmax,二者配对t检验,0.5 mg.kg-1和0.75mg.kg-1组差异无显著性(P>0.05);1.05 mg.kg-1组差异有显著性(P<0.05);比伐卢定序贯给药在给药后5 min和给药后4 h ACT值即ACT-5 min和ACT-4h进行配对t检验,结果显示差异无显著性(P>0.05),说明序贯给药开始5 min至4 h范围内,ACT值维持稳定。凝血功能(PA、PT、APTT、FIB)指标显示的抗凝血活性与给药剂量和血药浓度呈线性正相关。停药后ACT、PA、PT、APTT、FIB恢复至正常值范围。结论:国产注射用比伐卢定通过延长ACT、APTT、PT时间,同时抑制PA,呈现出与用药剂量和浓度线性相关的抗凝血活性,且静脉给药可立即产生抗凝血作用。停药后各项凝血指标即恢复至正常范围。     

直接凝血酶抑制剂研究进展

凝血酶处于凝血级联的重要位置,它在血小板活化和纤维蛋白生成中发挥重要作用.直接凝血酶抑制剂能够直接抑制凝血酶的活性,是一类非常有前景的抗血栓药物,本文对直接凝血酶抑制剂的研究进展进行综述.     

凝血酶抑制剂Flovagatran Sodium

Flovagatran Sodium（TGN-255）是英国Trigen公司开发的一种全合成、高效、可逆、低分子质量的直接凝血酶抑制剂,临床前研究结果显示其有较好的药动学特性及生物活性。当本品血药浓度为12mg·L^-1时,可使犬的活化凝血时间（activated clotting time,ACT）延长达480s,凝血酶时间（thrombin time,TY）延长达245s。     

国产比伐卢定在10名健康男性受试者体内的初步药动-药效学研究及安全性评价

目的初步研究国产比伐卢定在健康男性受试者体内的药动学和药效学特点并评价其安全性,为Ⅱ/Ⅲ期临床试验及临床应用提供科学依据。方法收集健康男性受试者,单次静脉弹丸式注射比伐卢定0.75 mg/kg,以液相色谱-串联质谱法测定给药后180 min内的血药浓度进行药动学分析,测定活化凝血时间进行药效学分析,同时观察给药前后受试者生命体征及安全性检查指标的变化。结果入选健康男性受试者10名,年龄(29.5±3.4)岁,身高(170.7±5.5)cm,体重(66±7)kg,体重指数(22.2±1.7)kg/m2。药动学参数:峰浓度(Cmax)为(8347±1586)μg/L,达峰时间(Tmax)为5 min,末端消除半衰期(T1/2z)为(41.6±9.0)min,0到t药时曲线下面积(AUC0-t)为124.0(98.4～182.3)min.μg/L,0到无穷药时曲线下面积(AUC0-∞)为(131.9±26.8)min.μg/L,平均驻留时间(MRT0-t)为(25.6±3.1)min,表观分布容积(Vz)为(354.8±103.9)ml/kg,清除率(CL)为(5.9±1.1)ml/(min.kg)。药效学参数:基础值(E0)为(146±17)s,半最大效应浓度(EC50)为2225(799～42 008)μg/L,最大效应(Emax)为(4072±294)s。试验结束后,所有受试者行X线胸片、头颅CT、12导联心电图及实验室检查(血尿常规、血生化、免疫、凝血5项检查),均未见异常。试验过程中受试者无不良反应发生。结论国产比伐卢定似有起效快和半衰期较短的特点,可作为一种较安全的抗凝剂用于经皮冠状动脉介入治疗的患者。     

比伐卢定在中国健康人群的药代动力学/药效学模型研究

目的 建立静脉注射比伐卢定药代动力/药效学(PK/PD)模型.方法 选36名健康受试者,男女各半,随机分为3组,分别单次静脉推注注射用比伐卢定0.50,0.75,1.05 mg·kg-1,在不同时间点监测血药浓度及活性凝血时间(ACT),用WinNonlin软件建立模型.结果 比伐卢定静脉注射二房室线性代谢药代动力学模型AIC值最小,药效学用有基础效应的M-M equation模型,建立比伐卢定PK/PD统一模型,模型数理参数分别为Vc=0.12,k10=3.54,k12=0.75,k21=1.44,E0=126.87,Emax=340.03,EC50=4258.03.经验证,不同剂量组比伐卢定PK/PD曲线预测值落在实测值的95％置信区间内,与实测值吻合良好.结论 建立的比伐卢定PK/PD模型有较好的适用性.     

比伐卢定在PCI治疗中的研究进展

冠心病是我国居民死亡的主要病因,经皮冠状动脉介入治疗手术（PCI）是快速有效解除心肌缺血状态,改善心肌循环的首选方法,有助于降低患者的病死率。此外,在PCI术中需要采用抗凝药物治疗,其是当下PCI手术治疗中不可或缺的重要部分,可直接影响手术的预后。PCI是冠心病和血管闭塞的一种常用支架疗法,其特点是疗程短、创伤小、疗效显著。随着近年来医疗技术的进步,新的抗凝药物与抗凝方案不断涌现。传统的抗凝药物普通肝素与新的药物比伐卢定之间孰优孰劣的讨论持续不断,二者均作为一线药物应用于临床,到目前为止,对何种药物作为首选仍无定论。本文通过对2种药物作用原理的异同和几个有代表性的大型研究（REPLACE-2、ISAR-REACT-3、ACUITY、HORIZONS-AMI、BRIGHT）进行总结归纳,为临床PCI抗凝治疗提供参考。     

注射用比伐卢定在中国健康受试者的耐受性研究

目的:初步评价注射用比伐卢定在中国人群的安全性和耐受性.方法:筛选48名中国健康受试者,男女各半,随机分为四组,分别单次静脉推注注射用比伐卢定0.5,0.75,1.05 mg·kg-1,或以0.75 mg·kg-1静推后,立即接续以1.75 mg·kg-1·h-1的速度匀速静滴4 h,观察给药前后受试者的临床症状、体征...     

直接凝血酶抑制剂的研究进展

该文主要介绍了几种凝血酶抑制剂的功能特点以及在国外的上市研究情况,为其将来在国内使用提供基本信息。     

Ximelagatran: the first oral direct thrombin inhibitor

Oral anticoagulants are often prescribed for long-term prevention and treatment of venous or arterial thromboembolism. The only orally active anticoagulants currently available are the vitamin K antagonists. Although effective, they have a narrow therapeutic window and require routine coagulation monitoring to ensure that a therapeutic level has been achieved. Furthermore, genetic differences in metabolism and multiple food and drug interactions affect the anticoagulant response to vitamin K antagonists. These factors add to the need for routine coagulation monitoring, which is problematic for patients and physicians and costly for the healthcare system. Ximelagatran, the first oral direct thrombin inhibitor, was designed to overcome many of the drawbacks of vitamin K antagonists. Since it produces a predictable anticoagulant response, ximelagatran does not require coagulation monitoring. Phase III clinical trials have evaluated the efficacy and safety of ximelagatran for the prevention and treatment of venous thromboembolism and for the prevention of thromboembolic events in patients with atrial fibrillation. Focusing on ximelagatran, this review will discuss the appropriateness of thrombin as a target for new anticoagulants, compare and contrast direct and indirect thrombin inhibitors and describe the theoretical advantages of direct thrombin inhibitors. It will also review the pharmacology of ximelagatran, discuss the clinical trial results with ximelagatran and provide perspective on the advantages and potential limitations of ximelagatran.     

Advances in the development of thrombin inhibitors

Thromboembolic diseases are a major cause of morbidity and mortality, particularly in the Western world, which has stimulated enormous research efforts by the pharmaceutical industry to introduce new antithrombotic therapies. One strategy is the development of direct inhibitors of the serine protease thrombin, which holds a central position in the final steps of the blood coagulation cascade and in platelet activation. At present there is only limited clinical use of some parenteral preparations of thrombin inhibitors in acute situations, especially when the common antithrombotic drugs heparin, warfarin and aspirin are ineffective or associated with side effects. However, for use in prophylaxis of thrombotic diseases such inhibitors should be orally available, must be safe to avoid bleeding complications and should have an appropriate half-life, allowing once or twice daily dosing to maintain adequate antithrombotically effective blood levels. Details of several new and potent thrombin inhibitors have been published during the last years. For some of them oral bioavailability is claimed and they are effective in in vitro coagulation assays. However, most of them showed only limited efficacy in animal studies with respect to the doses administered. For that reason, effort is concentrated on the evaluation and optimisation of the overall physicochemical characteristics of the inhibitors in order to improve the pharmacokinetics and, thus, the development of promising drug candidates. Nevertheless, only careful clinical studies can give clear answers about the true therapeutical benefit of new developments in this field. This review summarises the current status of direct thrombin inhibitors which are already in clinical use and clinical development and gives an overview on recently published and promising new compounds.     

直接凝血酶抑制药希美加群在心房颤动抗凝治疗中的应用

希美加群是一种直接凝血酶抑制药,具有抑制作用强、治疗窗口宽、为可逆性抑制、对游离的和与血栓结合的凝血酶均有抑制作用、起效较快等优点,在心房颤动抗凝治疗中发挥重要作用。     

新型凝血酶抑制剂阿加曲班

阿加曲班(argatroban)是一种凝血酶抑制剂,可直接与凝血酶的催化位点结合,迅速可逆的与凝血块结合并溶解凝血酶,其半衰期为39～51min,停止治疗后迅速恢复凝血功能,通过监测抗凝血参数调整其使用剂量.现介绍阿加曲班的药理学、药效学、药动学及不良反应、相互作用等方面的研究进展.     

Dabigatran etexilate,a new oral direct thrombin inhibitor,for stroke prevention in patients with atrial fibrillation

Importance of the field: Warfarin is the only oral anticoagulant recommended for the prevention of ischemic stroke in atrial fibrillation. A newer and safer anticoagulant is needed because of increased hemorrhagic risks with warfarin, difficult-to-maintain therapeutic levels, and higher drug to drug and food interactions.

Areas covered in this review: Dabigatran etexilate is a new, effective, reversible, rapid-acting, oral direct inhibitor of thrombin. This review focuses on the results of major Phase II and III trials conducted to evaluate the use of dabigatran in prevention of stroke in atrial fibrillation.

What the reader will gain: The objective of this paper is to discuss the use of dabigatran for prevention of stroke in patients with atrial fibrillation and to review its major advantages and disadvantages over warfarin.

Take home message: After the recent publication of Phase III trial RE-LY (randomized evaluation of long-term anticoagulation therapy), the use of dabigatran in atrial fibrillation is more clearly defined. A higher dose of dabigatran may be beneficial in patients who have recurrent ischemic events, despite therapeutic levels of warfarin. A lower dose is potentially safer than warfarin because of fewer hemorrhagic complications. Disadvantages include twice-daily dosing, dyspepsia and higher cost.     

Bivalirudin: a direct thrombin inhibitor

建立不同分离原理的高效液相色谱法,对7家企业的比伐芦定原料药中相关杂质进行分析,为全面控制比伐芦定有关物质提供依据。

采用反相高效液相色谱法(RP-HPLC)对11个杂质进行分离分析;采用亲水色谱法(HILIC-HPLC)对4个工艺杂质进行控制;采用分子排阻色谱法(SEC-HPLC)对聚合物进行测定。

建立的RP-HPLC方法可将主成分及11个杂质有效分离,11个杂质的校正因子均在0.8~1.2,比伐芦定检出浓度为0.1 μg·mL⁻¹,检测限为0.004%;建立的HILIC-HPLC方法可将主成分及4个工艺杂质有效分离,比伐芦定检出浓度为0.3 μg·mL⁻¹,检测限为0.01%;在SEC-HPLC条件下聚合物和比伐芦定依次出峰,两者分离度为2.9,比伐芦定检出浓度为6 ng·mL⁻¹,检测限为0.000 6%。采用主成分自身对照法计算7家企业15批样品中15种已知杂质及聚合物,不同企业的产品杂质含量与其生产工艺存在一定的相关性。

3种不同原理的方法均专属性良好,灵敏度高,耐用性好,结果可靠,可用于比伐芦定有关物质的质量控制。

     

Bivalirudin: a review

Bivalirudin (Angiomax®) is a thrombin-inhibiting oligopeptide that was developed via rational drug design as a hirudin analogue (‘hirulog’). Similar to hirudin, it is a bivalent thrombin inhibitor, as its 20-amino acid structure combines a carboxy-terminal region that recognises thrombin’s fibrin(ogen)-binding site, and an amino-terminal tetrapeptide that inhibits the active site of thrombin, connected by a tetraglycine spacer. It has certain pharmacological advantages over hirudin, including enzymic metabolism (less dependence on renal clearance) and low immunogenicity (reduced potential for anaphylaxis). Bivalirudin is approved for use in percutaneous transluminal coronary angioplasty (PTCA), and is undergoing active investigation for anticoagulation during cardiac surgery, both ‘off-pump’ and with cardiopulmonary bypass (‘on-pump’). Anecdotal ‘off-label’ experience for the treatment of heparin-induced thrombocytopenia shows promise.     

Bioequivalence of ximelagatran,an oral direct thrombin inhibitor,as whole or crushed tablets or dissolved formulation

SUMMARY

Objective: To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders.

Research design and methods: This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20–33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube.

Results: The plasma concentrations of ximelagatran, its intermediates and the active form melagatran were determined. Ximelagatran was rapidly absorbed and the bioavailability of melagatran was similar after the three different administrations, fulfilling the criteria for bioequivalence. The mean area under the plasma concentration-versus-time curve (AUC) of melagatran was 1.6μmol-h/l_ (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (Cmax) was 0.3μmol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t1/2) was 2.8?h for all treatments. The time to Cmax (tmax) was 2.2?h for the whole tablet and approximately 0.5?h earlier when the tablet was crushed or dissolved (1.7–1.8?h), due to a more rapid absorption. The study drug was well tolerated as judged from the low incidence and type of adverse events reported.

Conclusion: The present study showed that the pharmacokinetics (AUC and Cmax) of melagatran were not significantly altered whether ximelagatran was given orally as a crushed tablet mixed with applesauce or dissolved in water and given via nasogastric tube.