抗血小板药替格瑞洛的研究进展

替格瑞洛是新型环戊基三唑嘧啶类口服抗血小板药物,为选择性 P2Y12受体抑制剂,通过抑制新血凝块的形成,可降低动脉粥样硬化血栓形成事件的发生。替格瑞洛主要用于急性冠脉综合症抗血小板治疗和经皮冠状动脉介入治疗（PCI）中,具有强效、快速及可逆抑制血小板的特点,并且其本身具有活性不需经肝药酶活化,能够更好地防止缺血事件的发生。本文就替格瑞洛临床应用及不良反应做一综述,以为临床提供参考。     

新型抗凝血药替格瑞洛的合成

目的：高效合成抗凝血药替格瑞洛。方法4,6－二氯－2－（丙硫基）－5－硝基嘧啶在铁粉、乙酸作用下还原后与2－（（（3aR,4S,6R,6aS）－6－氨基－2,2－二甲基四氢－3aH－环戊〔d〕〔1,3〕二氧杂－4－基）氧基）乙醇经C－N偶联、重氮化成环,再与（1R,2R）－2－（3,4－二氟苯基）环丙胺亲核取代,最后酸解脱丙叉基保护得到替格瑞洛。结果与结论目标化合物的总收率约为55％,结构经1 H NMR和 MS确证。该合成路线反应步骤少,操作简便,反应条件温和,收率高,适合工业化生产。     

替格瑞洛药代动力学及血药浓度测定方法的研究现状

替格瑞洛可阻断血小板的活化和聚集,用于预防急性冠状动脉综合征和既往心肌梗死患者的血栓事件,其临床应用受制于不良事件的发生及个体差异。因此,替格瑞洛的血药浓度测定和药代动力学研究对于其临床合理应用十分必要。液相色谱-质谱联用技术是目前测定替格瑞洛及其活性代谢产物最广泛的检测方法之一。本综述就替格瑞洛的药代动力学特点及血药浓度测定方法进行概述,旨在为替格瑞洛治疗药物监测的开展提供参考。     

新型抗血小板药物替格瑞洛临床应用分析

目的:分析新型抗血小板药物替格瑞洛的临床应用。方法:选取2014年6月~2015年6月某院收治的114例患者为研究对象,随机分两组,各57例,对照组给予常规治疗,在此基础上,研究组给予替格瑞洛治疗,对比两组患者治疗效果。结果:随访1年,研究组的治疗总有效率、心血管事件发生率、不良反应发生率优于对照组,差异显著(P<0.05);研究组的治疗满意度、血小板聚集率均优于对照组,差异显著(P<0.05)。结论:临床上应用新型抗血小板药物替格瑞洛,保证了治疗效果,避免了并发症出现,利于患者早日康复,值得推广。     

新型抗血小板药物替格瑞洛临床应用分析

目的:分析住院患者替格瑞洛使用情况,了解该药物的临床应用现状,为提高替格瑞洛的临床合理用药水平提供参考。方法:收集北京大学第一医院2014年1~6月住院期间使用替格瑞洛病历资料,回顾性分析使用替格瑞洛患者的适应症、用法用量、相互作用及不良反应等。结果:纳入分析的患者共36例,男性24例,女性12例;平均年龄(63.77±14.69)岁;体重(70.76±11.17)kg。原发病均为急性冠脉综合征、PCI手术。36例患者中,4例为阿司匹林联用替格瑞洛,30例为阿司匹林联用氯吡格雷后将氯吡格雷更换为替格瑞洛,1例为阿司匹林联用西洛他唑后将西洛他唑更换为替格瑞洛,1例为阿司匹林加用替格瑞洛。31例患者按说明书中所示的用法用量使用,5种患者使用其他不同的用法用量。涉及的可能与替格瑞洛存在相互作用的合并用药共8种。共6例次出现相关不良反应,其中2例(5.56%)发生出血,4例(11.11%)出现呼吸困难。结论:我院替格瑞洛多应用于对氯吡格雷低反应或其他抗血小板药物出现不良反应的急性冠脉综合征患者。临床药师应严格把握该药用法用量,密切监测患者不良反应,促进替格瑞洛的合理应用。     

新型抗血小板聚集药物——替格瑞洛的研究进展

目的:为临床合理使用抗血小板聚集药物替格瑞洛提供参考。方法:归纳和整理近几年国内外有关替格瑞洛的文献报道和临床研究,对替格瑞洛药动学、药效学、安全性等方面的研究进展进行综述。结果:替格瑞洛为新型环戊基三唑嘧啶类药物,通过可逆性与血小板表面P2Y12受体结合抑制其与二磷酸腺苷结合,发挥抗血小板聚集作用。与氯吡格雷相比,具有起效迅速、停药后血小板功能恢复较快、有效降低心血管不良事件的发生等优势,同时不增加严重出血风险,具有很好的耐受性与安全性,且具有长期成本-效果优势。结论:替格瑞洛是一个很有潜力的新型血小板表面P2Y12受体拮抗药,在急性冠脉综合征治疗中优于氯吡格雷。     

药物基因多态性对替格瑞洛抗血小板聚集效果的影响

目的 在急性冠脉综合征（ACS）患者中开展替格瑞洛的药物基因组学研究,以期发现可以预测替格瑞洛抗血小板聚集效果个体差异的遗传学因素,为患者制定替格瑞洛的个体化用药方案提供参考。方法 对福建省某院2018年收治的75例符合纳入标准的汉族ACS患者进行DNA检测、血小板功能及聚集率检测。采用全外显子测序法检测入组患者的SLCO1B1、UGT2B7、P2Y12、PEAR1、ITGA2B、ITGB3的单核苷酸多态性。同时收集并记录患者的一般临床资料。通过单因素方差分析、多元线性回归分析等方法,分析替格瑞洛抗血小板效果与基因多态性的相关性。结果 单因素方差分析结果显示SLCO1B1 rs2306283 G等位基因可影响替格瑞洛抗血小板聚集效果,至少携带一个突变基因G的患者（AG型+GG型）平均最大血小板聚集率显著低于携带野生纯合子AA型的患者（8.07%±6.17%比13.88%±6.39%,P≤0.05）。而调整混杂因素后的多因素回归分析显示SLCO1B1 rs2306283 G等位基因并不是影响替格瑞洛抗血小板聚集效果的独立变量（P>0.05）。结论 在福建省汉族ACS患者中,与替格瑞...     

替格瑞洛在中国健康男性志愿者中的药动学及药效学研究

目的：研究替格瑞洛在中国健康志愿者中药动学及药效学,为其临床合理使用提供依据。方法：选14名健康男性志愿者,分别单次口服替格瑞洛180 mg,在不同时间点采集血样分别用于药动力学及药效学研究,其中药动学采样时间点为给药前、给药后0.5,1,1.5,2,3,4,5,6,8,12,16,24,36,48 h,药效学采样时间点为给药前他和给药后1,2,4,12,24,48 h,药动学血浆样品采用蛋白沉淀法处理,超高效液相色谱-串联质谱（UPLC-MS/MS）法测定原药、活性代谢产物浓度;药效学采用四通道血小板聚集仪测定ADP诱导的血小板聚集率,以血小板聚集抑制的变化程度作为替格瑞洛的药效学指标。用WinNonlin软件处理所得数据。结果：14例健康受试者口服180 mg替格瑞洛后,替格瑞洛原药、活性代谢产物AR-C124910XX在人体内平均t_max分别为（1.9±0.6）h和（2.1±0.6）h,平均t_1/2分别为（8.3±1.1）h和（9.7±2.5）h,平均C_max分别为（1 447.0±532.2）ng·mL^-1和（384.5±90.2）ng·mL^-1,平均AUC_0-last为（9 023.0±3 285.4）ng·mL^-1·h和（3 445.0±723.2）ng·mL^-1·h,平均AUC_0-∞为（9 208.7±3 437.6）ng·mL^-1·h和（3 594.4±827.0）ng·mL^-1·h。替格瑞洛对血小板抑制的达峰时间为4 h,对血小板抑制的最大效应E_max为（75.9±11.9%）。替格瑞洛的抗血小板效应随替格瑞洛及AR-C124910XX降低而减弱。结论：本研究系统考察了14例健康志愿者服用替格瑞洛后的药动学及药效学,为临床使用替格瑞洛剂量调整、优化治疗方案提供了理论依据。     

替格瑞洛的晶体结构研究

替格瑞洛是针对P2Y12受体开发成功的具有高效治疗急性冠状动脉综合症的药物,是一种非常有效的药物。本文主要对合成的替格瑞洛进行单晶X-射线衍射分析,应用SHELXTL-97晶体软件程序包通过直接法和最小二乘法来确定晶体结构和每一个手性碳原子的绝对构型。该晶体属于正交晶系,F₂₂₂空间群, a = 22.172(4) ?, b =34.185(9) ?,c =14.312(3) ?,V = 10848(4) ?₃,R₁ = 0.0811, wR₂ = 0.1978,Flack参数为-0.16(16)。     

新型抗血小板药替卡格雷

替卡格雷为第一个可逆结合的、直接起效的、口服给药的血小板二磷酸腺苷P2Y12受体拮抗剂,比氯吡格雷起效更快,对血小板凝集的抑制作用更强。2011年7月20日,美国FDA批准替卡格雷用于降低急性冠脉综合征(acute coronary syndrome,ACS)患者的血栓性心血管事件的发生率。与氯吡格雷相比,替卡格雷起效更快,对血小板聚集的抑制作用更强,能显著降低心血管死亡、心肌梗死或卒中的发生率。在有效治疗的同时,替卡格雷并未显著增加主要出血事件的发生率。联合用药时,阿司匹林的维持剂量应为75～100 mg.d-1。本文对替卡格雷药理学特性、临床价值及不良反应进行综述。     

Association of PEAR1 rs12041331 polymorphism and pharmacodynamics of ticagrelor in healthy Chinese volunteers

1.?Genetic polymorphisms in platelet endothelial aggregation receptor 1 (PEAR1) were associated with responsiveness to aspirin and P2Y12 receptor antagonists. This study aimed to investigate whether PEAR1 polymorphism is associated with ticagrelor pharmacodynamics in healthy Chinese subjects.

2.?The in vitro inhibition of platelet aggregation (IPA) was evaluated before and after ticagrelor incubated with platelet-rich plasma from 196 healthy Chinese male subjects. Eight polymorphisms at PEAR1 locus were genotyped. Eighteen volunteers (six in each rs12041331 genotype group) were randomly selected. After a single oral 180?mg dose of ticagrelor, plasma levels of ticagrelor and the active metabolite AR-C124910XX were measured and pharmacodynamics parameters including IPA and VASP-platelet reactivity index (PRI) were assessed.

3.?No significant difference in ticagrelor pharmacokinetics among rs12041331 genotype was observed. As compared with rs12041331?G allele carriers, AA homozygotes exhibited increased IPA after 15?μM ticagrelor incubation (p?p?p?4.?PEAR1 polymorphism may influence ticagrelor pharmacodynamics in healthy Chinese subjects.     

Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects

Aim

This study examined the effects of grapefruit juice on the new P2Y₁₂ inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein.

Methods

In a randomized crossover study, 10 healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90 mg dose of ticagrelor.

Results

Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (C_max) to 165% (95% confidence interval 147, 184%) and area under the concentration–time curve (AUC(0,∞)) to 221% of control (95% confidence interval 200, 245%). The C_max and AUC(0,34 h) (P < 0.05) but not the AUC(0,∞) of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity.

Conclusions

Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice–ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.     

基于PBPK建模预测替格瑞洛在人体内的药动学行为

目的:建立替格瑞洛在健康人群中的生理药动学(PBPK)模型,预测其口服给药后在人体的吸收部位与吸收量及组织分布特征,为预测替格瑞洛药物互相作用和临床治疗提供参考依据。方法:通过文献和ADMET Predictor软件计算获取替格瑞洛建模的理化参数及生物药剂学参数,通过替格瑞洛注射给药的药动学数据获取替格瑞洛在人体的清除率(CL),应用Gastro PlusTM软件建立替格瑞洛口服给药的PBPK预测模型,并对模型进行验证和优化。通过所建立的预测模型,能预测药物体内药-时曲线,预测药物吸收部位与吸收量及口服给药后药物在各个组织及器官中的药物暴露量。结果:模型拟合替格瑞洛的药-时曲线与实测值的平均折合误差(AFE)和绝对平均折合误差(AAFE)值分别为1.0和1.1,这表明所建立的PBPK模型有效性良好。药物主要的吸收部位为空肠,吸收量为35.8%。口服替格瑞洛后,药物在身体各个组织中均有广泛的分布,其在脂肪组织、红骨髓和黄骨髓中的药物显露量约是血中药物暴露量1.6倍。结论:所建立的PBPK模型可较好模拟替格瑞洛口服给药后的体内药动学行为,对于预测药物可能的相互作用及临床给药方案有指导意义。     

Review of pharmacoeconomic evaluation of genotype-guided antiplatelet therapy

Introduction: Clopidogrel is an antiplatelet agent widely prescribed for acute coronary syndrome (ACS), and it is activated by the CYP enzyme system to active metabolite. CYP2C19 loss-of-function (LOF) allele(s) affect the responsiveness of clopidogrel, but not the new antiplatelet agents (prasugrel and ticagrelor). We reviewed the pharmacoeconomic studies on genotype-guided use of new antiplatelet agents.

Areas covered: A literature search was conducted between the period of 2000 and 2014. Seven studies including cost-effectiveness and risk-benefit analyses of CYP2C19 genotype-guided antiplatelet therapy in ACS patients were reviewed. Genotype-guided prasugrel was found to be cost-effective when compared with universal antiplatelet therapy in four studies. Three studies showed genotype-guided ticagrelor to be cost-effective in ACS patients with percutaneous coronary intervention (PCI), and universal ticagrelor to be cost-effective in ACS patients. Drug cost of antiplatelet agents and relative risk of the new antiplatelet versus clopidogrel for clinical events were common influential factors of cost-effectiveness analyses.

Expert opinion: All studies in the present review focused on selecting antiplatelet agents for carriers of CYP2C19 LOF allele(s). Cost-effectiveness of genotype-guided use of antiplatelets was demonstrated in high-risk ACS patients.     

Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers

AIM

To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y₁₂ receptor antagonist, in healthy volunteers.

METHODS

This was a randomized, single-blind, placebo-controlled, ascending dose study. Thirty-two subjects received ticagrelor 50–600 mg once daily or 50–300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day⁻¹, or placebo for 14 days.

RESULTS

Ticagrelor was absorbed with median t_max 1.5–3 h, exhibiting predictable pharmacokinetics over the 50–600 mg dose range. Mean C_max and AUC for ticagrelor and its main metabolite, AR-C124910XX, increased approximately dose-proportionately (approximately 2.2- to 2.4-fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses ≥300 mg once daily and ≥100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor ≥100 mg twice daily was greater and less variable (93–100%, range 65–100%) than with clopidogrel (77%, range 11–100%) at trough concentrations. No safety or tolerability issues were identified.

CONCLUSIONS

Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50–600 mg once daily and 50–300 mg twice daily with C_max and AUC(0,t) increasing approximately dose-proportionally. Greater and more consistent IPA with ticagrelor at doses ≥100 mg twice daily and ≥300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day⁻¹ was well tolerated.     

The implications of genetic variation for the pharmacokinetics and pharmacodynamics of aromatase inhibitors

Introduction: Breast cancer is the most common female cancer and remains a serious public health concern worldwide. Third-generation aromatase inhibitors (AIs) are widely used in postmenopausal women with estrogen receptor positive breast cancer. However, there is marked interindividual variability in terms of the efficacy and incidence of adverse events following treatment with AIs. Pharmacogenetics has the potential to predict clinical outcomes based on patients’ genetic information, paving the way towards personalized treatment.

Areas covered: This article reviews pharmacogenetic studies of AIs, including pharmacokinetic and pharmacodynamic aspects, highlighting those studies where the efficacy and adverse events of AIs have been examined using both candidate gene and genome-wide approaches.

Expert opinion: Pharmacogenetics is a promising approach to develop personalized medicine with AIs. However, the application of pharmacogenetics to predict therapeutic efficacy and adverse events in breast cancer patients is still far from implementation in routine clinical practice. Large, comprehensive, multicenter studies that simultaneously evaluate multiple genes and pathways, including rare variants, are warranted in order to produce reliable and informative results. The ultimate aim is to develop clinically-relevant guidelines for breast cancer therapy.