AIS的治疗 - 安则诺医药

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弗拉基米尔 · 哈金斯基博士

脑细胞在卒中后迅速死亡，必须尽快开始有效的治疗[1]。从患者出现缺血性脑卒中的最初征兆到被成功治疗以减少脑损伤量的时间窗非常狭窄[2]。在此间隔内，成功治疗的可能性随着时间的流逝而降低[2]。时间就是大脑[3-6]！格言“时间就是大脑”强调应紧急进行治疗干预[5]。

治疗急性缺血性脑卒中(AIS)的主要方法有两种：血运重建和神经保护（脑保护）[7]。

血运重建包括三个独立的概念：血管再通（动脉开放）；再灌注（顺行的微血管灌注）；侧枝循环成形（绕过血管闭塞的主要部位，经软脑膜动脉或其他吻合动脉通道进行的微血管灌注）[8,34]。血运重建策略使用溶栓药物或血管内机械装置来再通闭塞的血管。早期再通仍然是最直观也是唯一被批准的逆转AIS动脉闭塞性缺血性损伤的有效治疗方法[9-11,32,33]。

然而，大多数缺血性卒中患者仍然得不到治疗或治疗不足，原因包括卒中发病时间不明、治疗时间窗狭窄或目前批准的治疗禁忌症很多等因素[12,13]。目前，只有5％–20％的AIS患者接受了血运重建治疗（溶栓治疗和/或血栓切除术）[14,15,18,20,35,36]。大多数患者，大约80%-95%的AIS患者不符合血运重建治疗的标准，而且对于这些患者，也没有有效的急性治疗方法[13-15]。因此，大多数AIS患者只得到支持性护理[15,36]。在这方面，血运重建治疗不能被视为AIS的突破性治疗，因为只有少数患者有资格接受这种治疗[16-22]。

虽然药物和机械血运重建疗法一般以完全的血管再通为目标，但下游再灌注并不总能实现[23,33]。在接受溶栓或血栓切除术的患者中，只有不到一半的患者从血运重建治疗中获得永久性收益，而高达三分之一的患者继续患有长期严重残疾[24]。即使成功地进行了血运重建治疗，AIS患者仍可能遭受缺血-再灌注损伤的固有风险[25]。

此外，由于目前的血运重建疗法需要主要在高级学术医疗中心才能找到的专家，而在较小的社区医院却很少见到，这使得血运重建疗法对于大多数患者而言都不是理想的治疗选择[26]。识别安全、有效、负担得起且易于应用的AIS治疗方法对公共卫生至关重要[27]。迫切需要探索更新的治疗途径。

因此，选择阻断缺血损伤级联反应的药物，能够安全地对更多的患者人群给药，是可取的[26]。然而，治疗AIS的神经保护剂的开发，其特点是动物研究的成功和随后的临床试验失败[28]。除了阿替普酶（r-tPA）是标准的溶栓疗法，也是西方国家唯一批准的治疗AIS的药物[20,29]外，临床前试验的神经保护剂，无论是作为单一治疗还是作为联合治疗，都没有转化为临床疗效[7,36]。

尽管到目前为止，临床试验屡次失败，但是脑保护仍然是AIS治疗的一个有希望的选择[30]。未满足的医疗需求、巨额的治疗费用、以及卒中后护理的巨大社会经济负担，使得脑保护和卒中康复方面哪怕取得微小的进步，都将带来极大的回报[31]。

参考文献

Audebert HJ, Saver JL, Starkman S, et al. Prehospital stroke care: new prospects for treatment and clinical research. Neurology. 2013; 81(5): 501-508.
Lindsay P, Cote R, Hill M, et al. The quality of stroke care in Canada. Ottawa: Canadian Stroke Network; 2011.
Gomez CR. Editorial: Time is brain! J Stroke Cerebrovasc Dis. 1993; 3(1): 1-2.
Hill MD, Hachinski V. Stroke treatment: time is brain. Lancet. 1998; 352(Suppl III): 10–14.
Saver JL. Time is brain–quantified. Stroke. 2006; 37: 263–266.
Yang SH, Lou M, Luo B, et al. Precision medicine for ischemic stroke, let us move beyond time is brain. Transl Stroke Res. 2018; 9(2): 93-95.
Fluri F, Schuhmann MK, Kleinschnitz C. Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther. 2015; 9: 3445-3454.
Wintermark M, Albers GW, Broderick JP, et al. Acute Stroke Imaging Research Roadmap II. Stroke 2013; 44(9): 2628-2639.
Liebeskind DS. Recanalization and reperfusion in acute ischemic stroke. F1000 Med Rep. 2010; 2: 71.
Tsivgoulis G, Katsanos AH, Alexandrov AV. Reperfusion therapies of acute ischemic stroke: potentials and failures. Front Neurol. 2014; 5: 215.
Smith WS, Furlan AJ. Brief History of Endovascular Acute Ischemic Stroke Treatment. Stroke 2016; 47(2): e23-26.
Gomis M, Dávalos A. Recanalization and Reperfusion Therapies of Acute Ischemic Stroke: What have We Learned, What are the Major Research Questions, and Where are We Headed? Front Neurol. 2014; 5: 226.
Overgaard K. The effects of citicoline on acute ischemic stroke: a review. J Stroke Cerebrovasc Dis. 2014; 23(7): 1764-1769.
Martynov MY, Gusev EI. Current knowledge on the neuroprotective and neuroregenerative properties of citicoline in acute ischemic stroke. J Exp Pharmacol. 2015; 7: 17-28.
Iadecola C, Anrather J. Stroke research at a crossroad: asking the brain for directions. Nat Neurosci. 2011; 14(11): 1363-1368.
Lapchak PA. Emerging Therapies: Pleiotropic Multi-target Drugs to Treat Stroke Victims. Transl Stroke Res. 2011; 2(2): 129-135.
Meyers PM, Schumacher HC, Connolly ES Jr, et al. Current status of endovascular stroke treatment. Circulation 2011; 123(22): 2591-2601.
Wardlaw JM, Dennis MS. Thrombectomy for Acute Ischemic Stroke. JAMA. 2015; 314(17): 1803-1805.
Cloft HJ, Rabinstein A, Lanzino G, et al. Intra-arterial stroke therapy: an assessment of demand and available work force. AJNR Am J Neuroradiol. 2009; 30(3): 453-458.
Badhiwala JH, Nassiri F, Alhazzani W, et al. Endovascular Thrombectomy for Acute Ischemic Stroke: A Meta-analysis. JAMA. 2015; 314(17): 1832-1843.
Henninger N, Fisher M. Extending the Time Window for Endovascular and Pharmacological Reperfusion. Transl Stroke Res. 2016; 7(4): 284-293.
van Wijngaarden JD, Dirks M, Huijsman R, et al. Hospital rates of thrombolysis for acute ischemic stroke: the influence of organizational culture. Stroke 2009; 40(10): 3390-3392.
Nour M, Scalzo F, Liebeskind DS. Ischemia-reperfusion injury in stroke. Interv Neurol. 2012; 1(3-4): 185-199.
Llull L, Amaro S, Chamorro Á. Administration of Uric Acid in the Emergency Treatment of Acute Ischemic Stroke. Curr Neurol Neurosci Rep. 2016; 16(1): 4
Bix GJ. Perlecan domain V therapy for stroke: a beacon of hope? ACS Chem Neurosci. 2013; 4(3): 370-374.
Turner RC, Dodson SC, Rosen CL, et al. The science of cerebral ischemia and the quest for neuroprotection: navigating past failure to future success. J Neurosurg. 2013; 118(5): 1072-1085.
Chang JJ, Mack WJ, Saver JL, et al. Magnesium: potential roles in neurovascular disease. Front Neurol. 2014; 5: 52.
Sena E, van der Worp HB, Howells D, et al. How can we improve the pre-clinical development of drugs for stroke? Trends Neurosci. 2007; 30(9): 433-439.
Acheampong P, Ford GA. Pharmacokinetics of alteplase in the treatment of ischaemic stroke. Expert Opin Drug Metab Toxicol. 2012; 8(2): 271-281.
Xiong XY, Liu L, Yang QW. Refocusing Neuroprotection in Cerebral Reperfusion Era: New Challenges and Strategies. Front Neurol. 2018; 9: 249.
Moretti A, Ferrari F, Villa RF. Neuroprotection for ischaemic stroke: current status and challenges. Pharmacol Ther. 2015; 146: 23-34.
Menon BK, Goyal M. Endovascular therapy in acute ischemic stroke: where we are, the challenges we face and what the future holds. Expert Rev Cardiovasc Ther. 2011; 9(4): 473-484.
Andonova S, Kirov F, Bachvarov C. The impact of recanalization on ischemic stroke outcome: A clinical case presentation. Perspect Med. 2012; 1: 455–458.
Tsai JP, Albers GW. Reperfusion versus recanalization: the winner is…. Stroke. 2015; 46(6): 1433-1434.
Lapchak PA, Zhang JH. The High Cost of Stroke and Stroke Cytoprotection Research. Transl Stroke Res. 2017; 8(4): 307-317.
Lapchak PA, Zhang JH. Neuroprotective Therapy for Stroke and Ischemic Disease. Cham, Switzerland: Springer, 2017.

治疗急性缺血性脑卒中(AIS)的主要方法有两种：血运重建和神经保护（脑保护）[7]。

参考文献

Audebert HJ, Saver JL, Starkman S, et al. Prehospital stroke care: new prospects for treatment and clinical research. Neurology. 2013; 81(5): 501-508.

Lindsay P, Cote R, Hill M, et al. The quality of stroke care in Canada. Ottawa: Canadian Stroke Network; 2011.

Gomez CR. Editorial: Time is brain! J Stroke Cerebrovasc Dis. 1993; 3(1): 1-2.

Hill MD, Hachinski V. Stroke treatment: time is brain. Lancet. 1998; 352(Suppl III): 10–14.

Saver JL. Time is brain–quantified. Stroke. 2006; 37: 263–266.

Yang SH, Lou M, Luo B, et al. Precision medicine for ischemic stroke, let us move beyond time is brain. Transl Stroke Res. 2018; 9(2): 93-95.

Fluri F, Schuhmann MK, Kleinschnitz C. Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther. 2015; 9: 3445-3454.

Wintermark M, Albers GW, Broderick JP, et al. Acute Stroke Imaging Research Roadmap II. Stroke 2013; 44(9): 2628-2639.

Liebeskind DS. Recanalization and reperfusion in acute ischemic stroke. F1000 Med Rep. 2010; 2: 71.

Tsivgoulis G, Katsanos AH, Alexandrov AV. Reperfusion therapies of acute ischemic stroke: potentials and failures. Front Neurol. 2014; 5: 215.

Smith WS, Furlan AJ. Brief History of Endovascular Acute Ischemic Stroke Treatment. Stroke 2016; 47(2): e23-26.

Gomis M, Dávalos A. Recanalization and Reperfusion Therapies of Acute Ischemic Stroke: What have We Learned, What are the Major Research Questions, and Where are We Headed? Front Neurol. 2014; 5: 226.

Overgaard K. The effects of citicoline on acute ischemic stroke: a review. J Stroke Cerebrovasc Dis. 2014; 23(7): 1764-1769.

Martynov MY, Gusev EI. Current knowledge on the neuroprotective and neuroregenerative properties of citicoline in acute ischemic stroke. J Exp Pharmacol. 2015; 7: 17-28.

Iadecola C, Anrather J. Stroke research at a crossroad: asking the brain for directions. Nat Neurosci. 2011; 14(11): 1363-1368.

Lapchak PA. Emerging Therapies: Pleiotropic Multi-target Drugs to Treat Stroke Victims. Transl Stroke Res. 2011; 2(2): 129-135.

Meyers PM, Schumacher HC, Connolly ES Jr, et al. Current status of endovascular stroke treatment. Circulation 2011; 123(22): 2591-2601.

Wardlaw JM, Dennis MS. Thrombectomy for Acute Ischemic Stroke. JAMA. 2015; 314(17): 1803-1805.

Cloft HJ, Rabinstein A, Lanzino G, et al. Intra-arterial stroke therapy: an assessment of demand and available work force. AJNR Am J Neuroradiol. 2009; 30(3): 453-458.

Badhiwala JH, Nassiri F, Alhazzani W, et al. Endovascular Thrombectomy for Acute Ischemic Stroke: A Meta-analysis. JAMA. 2015; 314(17): 1832-1843.

Henninger N, Fisher M. Extending the Time Window for Endovascular and Pharmacological Reperfusion. Transl Stroke Res. 2016; 7(4): 284-293.

van Wijngaarden JD, Dirks M, Huijsman R, et al. Hospital rates of thrombolysis for acute ischemic stroke: the influence of organizational culture. Stroke 2009; 40(10): 3390-3392.

Nour M, Scalzo F, Liebeskind DS. Ischemia-reperfusion injury in stroke. Interv Neurol. 2012; 1(3-4): 185-199.

Llull L, Amaro S, Chamorro Á. Administration of Uric Acid in the Emergency Treatment of Acute Ischemic Stroke. Curr Neurol Neurosci Rep. 2016; 16(1): 4

Bix GJ. Perlecan domain V therapy for stroke: a beacon of hope? ACS Chem Neurosci. 2013; 4(3): 370-374.

Turner RC, Dodson SC, Rosen CL, et al. The science of cerebral ischemia and the quest for neuroprotection: navigating past failure to future success. J Neurosurg. 2013; 118(5): 1072-1085.

Chang JJ, Mack WJ, Saver JL, et al. Magnesium: potential roles in neurovascular disease. Front Neurol. 2014; 5: 52.

Sena E, van der Worp HB, Howells D, et al. How can we improve the pre-clinical development of drugs for stroke? Trends Neurosci. 2007; 30(9): 433-439.

Acheampong P, Ford GA. Pharmacokinetics of alteplase in the treatment of ischaemic stroke. Expert Opin Drug Metab Toxicol. 2012; 8(2): 271-281.

Xiong XY, Liu L, Yang QW. Refocusing Neuroprotection in Cerebral Reperfusion Era: New Challenges and Strategies. Front Neurol. 2018; 9: 249.

Moretti A, Ferrari F, Villa RF. Neuroprotection for ischaemic stroke: current status and challenges. Pharmacol Ther. 2015; 146: 23-34.

Menon BK, Goyal M. Endovascular therapy in acute ischemic stroke: where we are, the challenges we face and what the future holds. Expert Rev Cardiovasc Ther. 2011; 9(4): 473-484.

Andonova S, Kirov F, Bachvarov C. The impact of recanalization on ischemic stroke outcome: A clinical case presentation. Perspect Med. 2012; 1: 455–458.

Tsai JP, Albers GW. Reperfusion versus recanalization: the winner is…. Stroke. 2015; 46(6): 1433-1434.

Lapchak PA, Zhang JH. The High Cost of Stroke and Stroke Cytoprotection Research. Transl Stroke Res. 2017; 8(4): 307-317.

Lapchak PA, Zhang JH. Neuroprotective Therapy for Stroke and Ischemic Disease. Cham, Switzerland: Springer, 2017.