阿替普酶
临床资料 | |
---|---|
商品名 | Activase、Actilyse、Cathflo Activase及其他。 |
其他名称 | t-PA, rt-PA |
AHFS/Drugs.com | Monograph |
核准状况 | |
怀孕分级 |
|
给药途径 | 静脉注射 |
ATC码 | |
法律规范状态 | |
法律规范 |
|
识别信息 | |
CAS号 | 105857-23-6 ![]() |
DrugBank | |
ChemSpider |
|
UNII | |
KEGG | |
化学信息 | |
化学式 | C2569H3928N746O781S40 |
摩尔质量 | 59,042.52 g·mol−1 |
阿替普酶(英语:Alteplase)以Activase等商品名称于市场中销售,是生物合成的人体组织型纤溶酶原激活剂(t-PA) 。它是一种溶栓药物,用于治疗急性缺血性中风、急性ST段上升型心肌梗塞、与低血压相关的肺栓塞和中央静脉导管阻塞。[5]透过静脉注射或动脉注射方式给药。[5]阿替普酶与血管内皮细胞产生的组织型纤溶酶原激活剂相同,[6]阿替普酶透过重组DNA技术于CHO细胞中合成,诱导纤溶作用而将血栓分解。[7]
此药物已被列入世界卫生组织基本药物标准清单内。[8]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/d/d1/%22Localisation_du_thrombus_et_cons%C3%A9quences_2%22_by_Servier_Medical_Art_is_licensed_under_CC_BY_2.0.jpg/220px-%22Localisation_du_thrombus_et_cons%C3%A9quences_2%22_by_Servier_Medical_Art_is_licensed_under_CC_BY_2.0.jpg)
医疗用途
[编辑]阿替普酶的作用与其他溶栓药物类似,适用于治疗急性缺血性中风、急性心肌梗塞、急性大面积肺栓塞和导管阻塞。[5][2][3]此药物可溶解血栓以恢复组织内血液流通,但结果会随病理情况而异。[9][10]药物通常是透过静脉注射进入人体。[7]而为处理导管阻塞,会将药物直接注入导管中。[7]
缺血性中风
[编辑]对于患有急性缺血性中风的成年人,标准做法是利用阿替普酶进行溶栓治疗。[10][11]采用阿替普酶与改善患者功能和降低失能发生率有关联。[12]阿替普酶与机械式取栓法联合使用会有更好的效果。[13][14]
肺栓塞
[编辑]迄2019年,阿替普酶是治疗肺栓塞最常用的药物。[15]输注阿替普酶所需时间不长(需2小时),它在人体中的生物半衰期为4-6分钟。[15]阿替普酶已获得美国食品药物管理局(FDA)核准透过新增的两种方式进行治疗:全身性溶栓 (systemic thrombolysis) 或导管导向溶栓术 (catheter-directed thrombolysis)。[15][16]
全身性溶栓可快速恢复急性肺栓塞患者的右心室功能、心率以及血压。[17]然而采用此治疗法时,使用的标准剂量可能会导致大出血(例如颅内出血),尤其是对于老年患者。[15]根据一项系统性回顾,显示低剂量阿替普酶比标准剂量会更安全,且同样有效。[18]
导管堵塞
[编辑]使用小剂量阿替普酶可清除受到堵塞导管中的血块,而能继续使用导管。[3][12]通常是使用中央静脉导管以侦测阻塞的部分。[19]目前美国医界处理导管堵塞的标准方法是施用阿替普酶。[6]阿替普酶在处理成人和儿童导管堵塞不但有效,且风险低。[6][19]整体而言,利用阿替普酶清除血栓的副作用很少见。[20]处理导管堵塞的新型替代药物(例如替奈普酶、瑞特帕酶和重组尿激酶),会比阿替普酶更快在血管内发挥作用。[19]
禁忌症
[编辑]个体经测试后如显示并非罹患急性缺血性中风,或是使用阿替普酶治疗的风险超过可能的益处,则不应施用此药物。[10]患有增加出血倾向的出血性疾患者,以及血小板计数异常低的患者禁用阿替普酶。[14]个体有活动性内出血和高血压的也禁用此药物。[14]阿替普酶在小儿科族群中的安全性尚未完全确定。[14]对于急性缺血性中风,如果个体已出现颅内出血和蛛网膜下腔出血时也要禁用。[21]ST段上升型心肌梗塞患者使用阿替普酶的禁忌与急性缺血性中风患者相似。[9]急性缺血性中风患者也可接受其他治疗方式,包括机械式取栓法。[10]
不良影响
[编辑]阿替普酶是种溶栓药物,使用后常见的不良反应就是出血,可能会致命。[22]阿替普酶的不良反应包括症状性颅内出血和致命性颅内出血。[22]
另一种不良反应是血管性水肿,如果导致气道阻塞,会有致命风险。[2]其他副作用可能很少,过敏反应是其中之一。[5]
作用机制
[编辑]![](http://upload.wikimedia.org/wikipedia/commons/thumb/1/16/Fibrinolysis.svg/220px-Fibrinolysis.svg.png)
阿替普酶与血块中的纤维蛋白结合,并活化血栓中的纤溶酶原。[7]阿替普酶在纤溶酶原的Arg561-Val562肽键位点将其裂解,形成纤溶酶。[7]纤溶酶是种纤维蛋白溶解酶,可裂解聚合纤维蛋白分子之间的交叉链接,导致血块散开及溶解,此过程称为纤溶作用。[7]
调节与抑制
[编辑]纤溶酶原激活剂抑制剂 1透过与阿替普酶结合并形成无活性复合物,而阻止阿替普酶的活性,血液中的此种复合物被肝脏清除。[7]由于纤溶酶抑制剂会灭活和调节纤溶酶活性,导致纤溶酶的纤溶作用的持续时间极短。[7]
历史
[编辑]美国国家神经疾患与中风研究所于1995年所做的一项研究,显示静脉注射阿替普酶可有效治疗缺血性中风,[23]而在医学界引发一场典范转移,医院急诊室的中风治疗因而被重新设计,以便及时评估和治疗缺血性中风的患者。[23]
社会与文化
[编辑]阿替普酶于2019年被列入世界卫生组织基本药物标准清单,用于治疗缺血性中风。[24][25]
法律地位
[编辑]由于FDA于1987年5月并未直接批准,而是要求药厂基因泰克再提供药物临床试验的额外数据,导致该公司股价为之下跌近四分之一。FDA此项要求被新闻描述为超出基因泰克以及许多心脏病专家和监管机构的意料之外,[26]且引发对FDA的严厉批评,其中包括来自《华尔街日报》编辑委员会的。[27][28]
经基因泰克提供额外两项临床试验的结果后,[27]此药物于1987年11月被批准用于治疗心肌梗塞。[5][2][29][30]距离此组织型纤溶酶原激活剂(t-PA)首次制成前后仅花费七年的时间,而成为史上最快开发成功的药物之一。[30]
经济学
[编辑]在2005年至2014年期间,于美国使用阿替普酶的成本增加111%,而其他类似作用处方药的成本并未照相同比例增加。[31]但阿替普酶仍具成本效益。[31]
品牌名称
[编辑]阿替普酶的商品名称有Actilyse、Activase和Cathflo(或称Cathflo Activase)。[2][3][32][33]
争议
[编辑]阿替普酶在低收入和中等收入国家的使用率极低。[34]原因可能是其成本高昂,而且通常并没健康保险覆盖其成本。[34]
关于使用阿替普酶治疗缺血性中风的文献中也可能存在引用偏倚的情况,因为报告组织纤溶酶原激活剂正面的结果,比报告负面或中性结果的研究更有可能在后续研究中受到引用。[35]
静脉注射组织纤溶酶原激活剂的使用存在健康上性别不平等,因为当女性发生急性缺血性中风时,使用该药物治疗的可能性会低于男性。[36]但此差异自2008年开始已持续改善中。[36]
参考
[编辑]- ^ Australian Public Assessment Report for Alteplase (AusPAR) (PDF). Therapeutic Goods Administration (TGA) (报告). February 2011 [2024-04-06]. (原始内容存档 (PDF)于2020-11-16).
- ^ 2.0 2.1 2.2 2.3 2.4 Activase- alteplase kit. DailyMed. 2018-12-05 [2020-01-04]. (原始内容存档于2017-01-11).
- ^ 3.0 3.1 3.2 3.3 Cathflo Activase- alteplase injection, powder, lyophilized, for solution. DailyMed. 2019-09-06 [2020-11-14]. (原始内容存档于2021-01-29).
- ^ Actilyse. European Medicines Agency. 2018-09-17 [2020-11-14]. (原始内容存档于2020-11-17).
- ^ 5.0 5.1 5.2 5.3 5.4 Alteplase Monograph for Professionals. Drugs.com. [2019-11-11]. (原始内容存档于2020-08-27).
- ^ 6.0 6.1 6.2 Baskin JL, Pui CH, Reiss U, Wilimas JA, Metzger ML, Ribeiro RC, Howard SC. Management of occlusion and thrombosis associated with long-term indwelling central venous catheters. Lancet. July 2009, 374 (9684): 159–69. PMC 2814365
. PMID 19595350. doi:10.1016/S0140-6736(09)60220-8.
- ^ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Jilani TN, Siddiqui AH. Tissue Plasminogen Activator. StatPearls. Treasure Island (FL): StatPearls Publishing. April 2020 [2020-11-10]. PMID 29939694. (原始内容存档于2021-01-29).
- ^ World Health Organization. The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. hdl:10665/371090
. WHO/MHP/HPS/EML/2023.02.
- ^ 9.0 9.1 O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. January 2013, 127 (4): e362–425. PMID 23247304. doi:10.1161/CIR.0b013e3182742cf6
.
- ^ 10.0 10.1 10.2 10.3 Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. December 2019, 50 (12): e344–e418. PMID 31662037. doi:10.1161/STR.0000000000000211
.
- ^ Powers WJ. Solomon CG , 编. Acute Ischemic Stroke. The New England Journal of Medicine. July 2020, 383 (3): 252–260. PMID 32668115. S2CID 220584673. doi:10.1056/NEJMcp1917030.
- ^ 12.0 12.1 Reed M, Kerndt CC, Nicolas D. Alteplase. StatPearls. Treasure Island (FL): StatPearls Publishing. 2020 [2020-10-30]. PMID 29763152. (原始内容存档于2021-01-29).
- ^ Mistry EA, Mistry AM, Nakawah MO, Chitale RV, James RF, Volpi JJ, Fusco MR. Mechanical Thrombectomy Outcomes With and Without Intravenous Thrombolysis in Stroke Patients: A Meta-Analysis. Stroke. September 2017, 48 (9): 2450–2456. PMID 28747462. S2CID 3751956. doi:10.1161/STROKEAHA.117.017320
.
- ^ 14.0 14.1 14.2 14.3 Demaerschalk BM, Kleindorfer DO, Adeoye OM, Demchuk AM, Fugate JE, Grotta JC, Khalessi AA, Levy EI, Palesch YY, Prabhakaran S, Saposnik G, Saver JL, Smith EE. Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. February 2016, 47 (2): 581–641. PMID 26696642. S2CID 9381101. doi:10.1161/STR.0000000000000086
.
- ^ 15.0 15.1 15.2 15.3 Ucar EY. Update on Thrombolytic Therapy in Acute Pulmonary Thromboembolism. The Eurasian Journal of Medicine //www.ncbi.nlm.nih.gov/pmc/articles/PMC6592452
|PMC=
缺少标题 (帮助). June 2019, 51 (2): 186–190. PMC 6592452. PMID 31258361. doi:10.5152/eurasianjmed.2019.19291
.
- ^ Martin C, Sobolewski K, Bridgeman P, Boutsikaris D. Systemic Thrombolysis for Pulmonary Embolism: A Review. P & T. December 2016, 41 (12): 770–775. PMC 5132419
. PMID 27990080.
- ^ Engelberger RP, Kucher N. Ultrasound-assisted thrombolysis for acute pulmonary embolism: a systematic review. European Heart Journal. March 2014, 35 (12): 758–64. PMID 24497337. doi:10.1093/eurheartj/ehu029
.
- ^ Zhang Z, Zhai ZG, Liang LR, Liu FF, Yang YH, Wang C. Lower dosage of recombinant tissue-type plasminogen activator (rt-PA) in the treatment of acute pulmonary embolism: a systematic review and meta-analysis. Thrombosis Research. March 2014, 133 (3): 357–63. PMID 24412030. doi:10.1016/j.thromres.2013.12.026.
- ^ 19.0 19.1 19.2 Baskin JL, Reiss U, Wilimas JA, Metzger ML, Ribeiro RC, Pui CH, Howard SC. Thrombolytic therapy for central venous catheter occlusion. Haematologica //www.ncbi.nlm.nih.gov/pmc/articles/PMC3342964
|PMC=
缺少标题 (帮助). May 2012, 97 (5): 641–50. PMC 3342964. PMID 22180420. doi:10.3324/haematol.2011.050492
.
- ^ Hilleman D, Campbell J. Efficacy, safety, and cost of thrombolytic agents for the management of dysfunctional hemodialysis catheters: a systematic review. Pharmacotherapy. October 2011, 31 (10): 1031–40. PMID 21950645. S2CID 2092899. doi:10.1592/phco.31.10.1031.
- ^ Parker S, Ali Y. Changing contraindications for t-PA in acute stroke: review of 20 years since NINDS. Current Cardiology Reports. October 2015, 17 (10): 81. PMID 26277361. S2CID 26427160. doi:10.1007/s11886-015-0633-5.
- ^ 22.0 22.1 Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, Cohen G, Davis S, Donnan G, Grotta J, Howard G, Kaste M, Koga M, von Kummer R, Lansberg M, Lindley RI, Murray G, Olivot JM, Parsons M, Tilley B, Toni D, Toyoda K, Wahlgren N, Wardlaw J, Whiteley W, del Zoppo GJ, Baigent C, Sandercock P, Hacke W. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet //www.ncbi.nlm.nih.gov/pmc/articles/PMC4441266
|PMC=
缺少标题 (帮助). November 2014, 384 (9958): 1929–35. PMC 4441266. PMID 25106063. doi:10.1016/S0140-6736(14)60584-5
.
- ^ 23.0 23.1 Campbell BC, Meretoja A, Donnan GA, Davis SM. Twenty-Year History of the Evolution of Stroke Thrombolysis With Intravenous Alteplase to Reduce Long-Term Disability. Stroke. August 2015, 46 (8): 2341–6. PMID 26152294. S2CID 207614164. doi:10.1161/STROKEAHA.114.007564.
- ^ World Health Organization. World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. hdl:10665/325771
. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- ^ World Health Organization. Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. Geneva: World Health Organization. 2019. hdl:10665/325773
. WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO.
- ^ Sun, Marjorie. FDA Puts New Heart Drug on Hold: A surprise decision by the FDA to withhold approval of TPA, a potent clot-dissolving drug, highlights a scientific debate among cardiologists. Science. 1987-07-03, 237 (4810): 16–18. PMID 3110948. doi:10.1126/science.3110948.
- ^ 27.0 27.1 Carpenter, Daniel P. Reputation and power : organizational image and pharmaceutical regulation at the FDA. Princeton: Princeton University Press. 2010: 2–7. ISBN 9780691141794.
- ^ Sun, Marjorie. Heart Drug in Limbo. The Washington Post. 1987-07-28 [2023-03-03].
- ^ Activase: FDA-Approved Drugs. U.S. Food and Drug Administration (FDA). [2020-01-04]. (原始内容存档于2020-08-27).
- ^ 30.0 30.1 Collen D, Lijnen HR. The tissue-type plasminogen activator story. Arteriosclerosis, Thrombosis, and Vascular Biology. August 2009, 29 (8): 1151–5. PMID 19605778. doi:10.1161/ATVBAHA.108.179655
.
- ^ 31.0 31.1 Kleindorfer D, Broderick J, Demaerschalk B, Saver J. Cost of Alteplase Has More Than Doubled Over the Past Decade. Stroke. July 2017, 48 (7): 2000–2002. PMID 28536176. S2CID 3729672. doi:10.1161/strokeaha.116.015822
.
- ^ Cathflo Activase Uses, Side Effects & Warnings. Drugs.com. [16 November 2020]. (原始内容存档于22 September 2020).
- ^ Collen D, Lijnen HR. Tissue-type plasminogen activator: a historical perspective and personal account. Journal of Thrombosis and Haemostasis. April 2004, 2 (4): 541–6. PMID 15102005. S2CID 42654928. doi:10.1111/j.1538-7933.2004.00645.x.
- ^ 34.0 34.1 Khatib R, Arevalo YA, Berendsen MA, Prabhakaran S, Huffman MD. Presentation, Evaluation, Management, and Outcomes of Acute Stroke in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis. Neuroepidemiology. 2018, 51 (1–2): 104–112. PMC 6322558
. PMID 30025394. doi:10.1159/000491442.
- ^ Misemer BS, Platts-Mills TF, Jones CW. Citation bias favoring positive clinical trials of thrombolytics for acute ischemic stroke: a cross-sectional analysis. Trials. September 2016, 17 (1): 473. PMC 5039798
. PMID 27677444. S2CID 9343300. doi:10.1186/s13063-016-1595-7
.
- ^ 36.0 36.1 Strong B, Lisabeth LD, Reeves M. Sex differences in IV thrombolysis treatment for acute ischemic stroke: A systematic review and meta-analysis. Neurology. July 2020, 95 (1): e11–e22. PMID 32522796. S2CID 219586256. doi:10.1212/wnl.0000000000009733.
|