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中药注射剂对华法林抗凝作用的影响及相关机制的研究进展

花匠小妙招
2025-03-04 19:34

[1]康俊萍. 华法林临床应用要点[J].中国医刊,2014,49(1):11-14.[本文引用:1][2]肖幸,周仑,高翔.41例服用华法林老年患者国际标准化比值异常变化的药物因素[J].医药导报,2018,37(1):107-109.[本文引用:1][3]殷硕,于月,郭兴蕾,等.中药对华法林作用的影响及机制概述[J].中国临床药理学与治疗学,2015,20(3):327-334.

华法林是临床常用的一种香豆素类口服抗凝药，具有蛋白结合率高、依赖细胞色素P450酶代谢及治疗窗窄等特点，易与其他药物发生相互作用，造成患者出血风险增加或抗凝治疗不足等严重后果。中药在治疗心脑血管疾病等方面具有独特的优势，临床应用广泛，与华法林合用的机会较多。本文根据已有的实验研究和临床案例报道，分别对单味中药及中药复方制剂对华法林抗凝作用的影响及相关机制进行了综述和探讨，以期为临床合理用药和相关研究提供参考。

Magsci

[本文引用:1][4]王晓蕊,毛静远.中药影响华法林抗凝作用的研究进展[J].中西医结合心脑血管病杂志,2016,14(20):2379-2383.

中药临床应用日益广泛，与华法林合用增多，中药可能通过影响华法林与血浆蛋白的结合、影响 CYP450酶的活性、影响转运体作用干扰华法林代谢而影响抗凝效果；中药本身具有抗凝或抗血小板聚集作用与华法林合用产生协同作用而增强抗凝效果。本文总结近年来影响华法林抗凝作用的中药及可能机制，为临床合理用药提供参考。

DOI:10.3969/j.issn.1672-1349.2016.20.013 URL

[本文引用:1][5]杜娟. 65例常用中药注射剂不良反应原因分析及临床对策[J].海峡药学,2012,24(10):265-266.[本文引用:1][6]周庆,伍三兰,韩勇.华法林导致皮下严重出血的药学监护[J].医药导报,2016,35(4):427-428.

目的探讨临床药师在心房颤动患者使用华法林抗凝治疗中进行药学服务的途径和方式方法,提高治疗效果。方法 1例心房颤动患者使用华法林抗凝治疗期间,未定期监测国际标准化比值,未及时调整剂量,导致消化道出血和皮下严重出血,伴有感染症状。临床药师根据相关用药指南,与临床医师共同商讨制定个体化治疗方案,对患者实施全程的药学监护,包括维生素K1的合理剂量以及再次使用抗凝药的条件。结果临床药师对出血后的处理措施及出血后再次使用抗凝药的条件给医生提供合理化建议;对患者可能出现的出血与血栓风险进行评估并给予药学监护。结论临床药师积极参与临床合理用药,给予医师相应的建议,以确保患者用药安全有效,在抗凝血药的合理应用中发挥积极作用。

DOI:10.3870/j.issn.1004-0781.2016.04.025

[本文引用:1][7]耿强,郭丹杰.65岁以上老年患者口服华法林抗凝的安全性探讨[J].中西医结合心脑血病杂志,2009,7(7):834-835.[本文引用:1][8]HYLEK E M,EVANS-MOLINA C,SHEA C,et al.Major hemorrhage and tolerability of wafarin in first year of therapy among elderly patients with atrial fibrillation[J].Circulation,2007,115(21):2689-2696.

Abstract BACKGROUND: Warfarin is effective in the prevention of stroke in atrial fibrillation but is under used in clinical care. Concerns exist that published rates of hemorrhage may not reflect real-world practice. Few patients > or = 80 years of age were enrolled in trials, and studies of prevalent use largely reflect a warfarin-tolerant subset. We sought to define the tolerability of warfarin among an elderly inception cohort with atrial fibrillation. METHODS AND RESULTS: Consecutive patients who started warfarin were identified from January 2001 to June 2003 and followed for 1 year. Patients had to be > or = 65 years of age, have established care at the study institution, and have their warfarin managed on-site. Outcomes included major hemorrhage, time to termination of warfarin, and reason for discontinuation. Of 472 patients, 32% were > or = 80 years of age, and 91% had > or = 1 stroke risk factor. The cumulative incidence of major hemorrhage for patients > or = 80 years of age was 13.1 per 100 person-years and 4.7 for those or = 80 years, and international normalized ratio (INR) > or = 4.0 were associated with increased risk despite trial-level anticoagulation control. Within the first year, 26% of patients > or = 80 years of age stopped taking warfarin. Perceived safety issues accounted for 81% of them. Rates of major hemorrhage and warfarin termination were highest among patients with CHADS2 scores (an acronym for congestive heart failure, hypertension, age > or = 75, diabetes mellitus, and prior stroke or transient ischemic attack) of > or = 3. CONCLUSIONS: Rates of hemorrhage derived from younger noninception cohorts underestimate the bleeding that occurs in practice. This finding coupled with the short-term tolerability of warfarin likely contributes to its underutilization. Stroke prevention among elderly patients with atrial fibrillation remains a challenging and pressing health concern.

DOI:10.1161/CIRCULATIONAHA.106.653048 PMID:17515465 URL

[本文引用:1][9]李乐,程欣,王晶晶.中药注射剂与华法林药物相互作用的研究进展[J].中国老年保健医学,2016,14(3):59-61.[本文引用:1][10]刘燕,李振洲,曹燕滔,等.疏血通注射液和华法林联用致国际标准化比率升高[J].药物不良反应杂志,2007,9(3):217-218.

53岁女性患甲亢、心房颤动17年,入院后因头晕和血栓史,给予疏血通注射液8ml静脉滴注,1次/d。患者1年前患脑梗死,口服华法林片3.125mg,1次/d,国际标准化比率(INR)在1.9～2.5之间。入院治疗2周后复查凝血酶原时间49.7s,凝血酶原活动度12.3%,部分凝血活酶时间74.8s,INR3.70,PLT254×109/L。停用疏血通并将华法林3mg,1次/d改为1.5mg,1次/d。3d后复查凝血酶原时间24.3s,INR1.91。恢复华法林3mg,1次/d,患者无出血症状

Magsci

[本文引用:1][11]张德隆,王洪志.一例华法林与注射用丹参多酚酸盐合用致眼结膜出血的病例分析[J].首都食品与医药,2018,25(15):66.[本文引用:1][12]谢红娟,付海英,朱彩凤,等.丹参注射液对大鼠体内稳态华法林药动学和药效学参数的影响[J].医药导报,2009,28(1):36-40.[本文引用:1][13]李婷婷,刘艳,冯立影,等.刺五加注射液对大鼠华法林抗凝作用的影响[J].实用药物与临床,2015,18(11):1280-1283.[本文引用:1][14]杜立峰,郑海燕,王鹏.注射用血栓通对华法林在大鼠体内药效学和药动学的影响[C].基层医疗机构从业人员科技论文写作培训会议论文集,2016.[本文引用:1][15]冯立影,梁晓玲,李婷婷,等.丹红注射液对大鼠体内华法林抗凝作用的影响[J].中国药师,2016,19(1):1-4.[本文引用:1][16]赵海峰,孙佳慧,刘爽,等.疏血通注射液对大鼠体内华法林抗凝作用的影响[J].中国中药杂志,2017,42(5):982-988.[本文引用:1][17]LIU Y,LIU S,SHI Y,et al.Effects of safflower injection on the pharmacodynamics and pharmacokinetics of warfarin in rats[J].Xenobiotic,2018,48(8):818-823.

DOI:10.1080/00498254.2017.1361051 URL

[本文引用:1][18]SUN J,LU Y,LI Y,et al.Influence of shenxiong glucose injection on the activities of six CYP isozymes and metabolism of warfarin in rats assessed using probe cocktail and pharmacokinetic approaches[J].Molecules,2017,22(11):1994.

DOI:10.3390/molecules22111994 URL

[本文引用:0][19]谭毓治,伍爱婵,谭丙炎,等.小檗碱竞争血浆蛋白结合部位所致药物相互作用的研究[J].中国药理学通报,2002,28(5):576-578.[本文引用:1][20]卜明华,郑咏秋,张颖,等.参麦注射液和注射用血塞通对大鼠肝脏及肠道药物代谢酶P450的影响[J].中国临床药理学杂志,2012,28(1):49-51.[本文引用:3][21]于初楚,胡冰,褚杨,等.注射用益气复脉(冻干)对大鼠肝微粒体CYP1A2,CYP3A4活性的影响研究[J].中国中药杂志,2011,10(36):1378-1381.[本文引用:2][22]石杰,陈安进,张芳,等.血塞通及川芎嗪对细胞色素P450不同亚型代谢酶影响的研究[J].中国中西医结合急救杂志,2008,15(6):342-345.[本文引用:1][23]LIU R,QIN M N,HANG P Z,et al.Effects of Panax Notoginseng saponins on the activities of CYP1A2,CYP2C9,CYP2D6 and CYP3A4 in rats in vivo[J].Phytother Res,2012,26(8):1113-1118.

The aim of this study was to assess the influence of the Panax notoginseng saponins (PNS) on the activities of the drug-metabolizing enzymes cytochrome P450 (CYP450) 1A2, 265C9, 2D6 and 3A4 in rats. The activities of CYP1A2, 265C9, 2D6 and 3A4 were measured using specific probe drugs. After pretreatment for 165week with PNS or physiological saline (control group), probe drugs caffeine (1065mg/kg; CYP1A2 activity), tolbutamide (1565mg/kg; CYP2C9 activity), metoprolol (2065mg/kg; CYP2D6 activity) and dapsone (1065mg/kg; CYP3A4 activity) were administered to rats by intraperitoneal injection. The blood was then collected at different times for ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) analysis. The data showed that PNS exhibited an induction effect on CYP1A2 by decreasing caffeine Cmax (36.3%, p65<650.01) and AUC0-∞ (22.77%, p65<650.05) and increasing CL/F (27.03%, p65<650.05) compared with those of the control group. Western blot analysis was used to detect the effect of PNS on the protein level of CYP1A2, and the results showed that PNS could upregulate the protein expression of CYP1A2. However, no significant changes in CYP2C9, 2D6 or 3A4 activities were observed. In conclusion, the results indicate that PNS could induce CYP1A2, which may affect the disposition of medicines primarily dependent on the CYP1A2 pathway. Our work may be the basis of related herb–drug interactions in the clinic. Copyright 08 2011 John Wiley & Sons, Ltd.

DOI:10.1002/ptr.3688 PMID:22162298 URL

[本文引用:1][24]卫常松. 金纳多对大鼠肝脏细胞色素P450酶活性的影响[J].山东医药,2008,40(48):6.[本文引用:1][25]张咏莉. 黄芪颗粒和黄芪注射液对CYP1A2、CYP2D、CTP2C亚酶活性影响的实验研究[J].中国药理学通报,2013,29(4):512-519.[本文引用:1][26]YU Y,LIU Y,LI Q,et al.Effects of Guanxinning injection on rat cytochrome P450 isoforms activities in vivo and in vitro[J].Xenobiotic,2015,45(6):481-487.

DOI:10.3109/00498254.2014.993002 URL

[本文引用:1][27]简瞰昱. 五种滇产中药主要药效成分及灯盏花素注射液对大鼠CYP1A2体内外抑制活性研究[D].昆明:昆明医学院,2011:21-34.[本文引用:1][28]赵文婷,张波,李湘晖,等.疏血通注射液对大鼠细胞色素P450酶6种亚型活性的影响[J].中药新药与临床药理,2012,23(4):445-449.[本文引用:2][29]余小翠,黄丽军,刘高峰,等.丹红注射液对大鼠肝微粒体5种CYP亚型酶活性的影响[J].医药导报,2012,31(3):277-281.[本文引用:2][30]陈为烤. 脉络宁注射液的代谢性药物相互作用研究[D].南京:南京中医药大学,2009:31-49.[本文引用:1][31]叶林虎. 醒脑静注射液对人肝微粒体P450酶5种亚型体外抑制作用[J].中国新药与临床杂志,2016,35(7):512-517.[本文引用:1][32]秦梦楠,刘蕊,刘高峰,等.灯盏花素注射液对大鼠体外肝微粒体细胞色素P450酶活性的影响[J].中国药师,2012,15(2):147-150.[本文引用:1][33]许黎君,居文政,陈为烤,等.灯盏细辛注射液对小鼠肝微粒体细胞色素P450含量的影响[J].中国临床药理学与治疗学,2008,13(10):1122-1126.[本文引用:1][34]韩永龙,余奇,孟祥乐,等.灯盏细辛注射液对大鼠肝微粒体CYP3A的抑制作用[J].中国临床药理学与治疗学,2009,14(8):891-895.[本文引用:1][35]韩永龙,孟祥乐,李丹,等.清开灵注射剂等5种中药注射剂对对大鼠肝微粒体CYP3A的体外抑制作用[J].中国中药杂志,2011,36(4):492-495.[本文引用:3][36]XIA C H,SUN J H,WANG G J,el al.Herbdrug interac-tion:in vivo and in vitro effect of Shenmai injection,a herbal preparation,on the metabolic activities of hepatic cyochrome P450 3A1/2,2C6,1A2 and 2E1 in rats[J].Planta Med,2010,76(3):245-250.

DOI:10.1055/s-0029-1186082 URL

[本文引用:1][37]韩淑燕,周宁,李萍萍,等.消癌平注射液通过调控CYP450酶抑制吉非替尼代谢而改善其耐药的作用及机理研究[C].2012年屮国药学大会暨第十二届中国药师周论文集,2012.[本文引用:1][38]叶林虎,贺梅,常琪,等.喜炎平注射液对人肝微粒体P450酶活性的影响[J].中国临床药理学杂志,2014,30(9):797-799.[本文引用:1][39]曾超,刘艳,刘高峰,等.刺五加注射液对大鼠肝微粒体四种CYP450亚型酶活性的影响[J].中国临床药理学与治疗学,2012,17(2):164-170.

目的：研究刺五加注射液在大鼠体外肝微粒体中对CYP2C9、CYP2D6、CYP2E1和CYP3A4活性的影响，为临床合理联合用药提供参考。方法：在大鼠体外肝微粒体中分别加入四种亚型酶的探针药物甲苯磺丁脲(TB)、右美沙芬(DM)、氯唑沙宗(CLZ)、睾酮(TS)和低、中、高剂量的刺五加注射液，温孵后用HPLC法测定各空白对照组和不同剂量刺五加注射液给药组中各探针药物代谢产物的浓度并比较代谢率的差异，以评价刺五加注射液对各亚型酶活性的影响；中剂量组活性显著降低的亚型酶进一步考察抑制作用的强弱(即IC50和Ki值)。结果：与空白对照组比较，刺五加注射液低、中、高剂量给药组对CYP3A4活性的影响均有统计学意义(P < 0.01)，抑制率分别为10.22%、19.00%、30.29%，其IC50和Ki值分别为3.96%和2.74%(V/V)；低、中、高剂量给药组对CYP2D6活性的影响均无统计学差异(P > 0.05)；低剂量给药组对CYP2C9、CYP2E1活性的影响无统计学差异(P > 0.05)，中、高剂量给药组对两个亚型的抑制作用有统计学意义(P < 0.05)，但中剂量给药组抑制率均小于8.50%，高剂量给药组抑制率均小于12.00%。结论：刺五加注射液对大鼠体外肝微粒体CYP3A4有抑制作用，且符合混合型抑制模型；对CYP2C9、CYP2E1抑制作用较弱；对CYP2D6活性无影响。

DOI: Magsci

[本文引用:1][40]郑林. 参芎葡萄糖注射液药效物质基础及作用机制研究[D].贵阳:贵阳医学院,2015:87-119.[本文引用:1][41]毕绮丽,古淑仪,吴苑珊.银杏叶注射剂对华法林抗凝效果的影响[J].现代医院,2011,11(3):6-7.[本文引用:0][42]毕绮丽,吴苑珊,邝剑文.银杏叶注射剂与华法林药效学相互作用的临床研究[J].现代医院,2014,14(5):76-77.[本文引用:0][43]马莉,符业阳,刘月玲.注射用灯盏花素联合华法林治疗永久性心房颤动随机平行对照研究[J].海南医学,2016,27(13):2093-2095.[本文引用:0][44]于萍. 丹红注射液联合华法林在房颤合并冠心病患者治疗中的作用[J].血栓与止血学,2018,24(3):444-446.[本文引用:0][45]任涛,丁礼仁,姜伟敏.血栓通注射液联合华法林、低分子肝素治疗急性肺血栓栓塞症的临床观察[J].中国药房,2014,25(44):4190-4192.

目的:观察血栓通注射液联合法华林、低分子肝素治疗急性肺血栓栓塞症(PTE)的临床疗效和安全性。方法:将152例PTE患者随机均分为对照组和试验组。两组患者均予以卧床休息、吸氧等常规治疗。与此同时,对照组患者给予华法林3~5 mg,口服,qd+低分子肝素7 500 U,皮下注射,bid;试验组患者在对照组治疗的基础上给予血栓通注射液140 mg加入0.9%氯化钠注射液100 ml中静脉滴注,qd。两组患者疗程均为14 d。观察两组患者的临床疗效,治疗前后动脉血酸碱度(p H)、动脉血氧分压[pbt(O2)]、动脉血二氧化碳分压[pbt(CO2)]等肺动脉血气指标,缺损肺动脉栓塞数及改善率,随访两组患者6个月再入院率和病死率,记录不良反应发生情况。结果:试验组患者总有效率、缺损肺动脉栓塞数改善率均显著高于对照组,两组比较差异有统计学意义(P0.05)。治疗前两组患者p H、pbt(O2)、pbt(CO2)、缺损肺动脉栓塞数比较,差异均无统计学意义(P0.05);治疗后两组患者p H、缺损肺动脉栓塞数均显著低于同组治疗前,且试验组低于对照组,pbt(O2)、pbt(CO2)均显著高于同组治疗前,且试验组高于对照组,差异均有统计学意义(P0.05)。两组患者再入院率、病死率、不良反应发生率比较,差异均无统计学意义(P0.05)。结论:血栓通注射液联合华法林、低分子肝素治疗PTE较华法林联合低分子肝素疗效更好,安全性相似。

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