替罗非班联合尿激酶血管内超选择溶栓的实验及临床研究
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摘要
脑血管疾病(cerebrovascular disease, CVD)是神经系统的常见病和多发病,死亡率占所有疾病的10%,是目前人类因疾病死亡的三大原因之一。在我国,每年死于脑卒中的人数超过100万,占我国人口死因的首位(占22.45%),50%-70%的存活者留有瘫痪、失语等严重后遗症,给社会和家庭带来沉重负担。脑血管疾病可分为缺血性卒中和出血性卒中。缺血性卒中是目前最常见的,约占中风的80%-90%。缺血性卒中是以脑局部血液循环障碍、血流量减少为特征的一种病变。据统计,缺血性中风70%以上是由颅内或颅外大血管的急性阻塞引起。因此,尽快恢复缺血区的血流灌注是急性缺血性中风治疗的基本原则,溶栓治疗正是在此基础上建立起来的行之有效的方法。传统观念认为早期主要采取溶栓治疗,时间窗为3小时以内,旨在使闭塞动脉再通来恢复缺血区的血流灌注,以拯救尚能存活的脑组织,改善病人预后。目前,以组织型纤溶酶原激活剂为基础的急性溶栓治疗,是唯一通过美国食品及药品管理局认证的方法,已被越来越多的临床医生接受并应用于临床。与此同时也带来了一些溶栓相关的问题,如颅内出血、再闭塞和缺血再灌注损伤等并发症。静脉内溶栓治疗,颅内血管部分或完全再通率,颈内动脉仅10%,大脑中动脉约为25%。出血和血管再闭塞是影响溶栓治疗的主要原因。特别是症状性出血,有较高的发生率(6%)和严重的后果迫使医学工作者对这一方法重新审视。尽管试验结果再次证实了急性期溶栓治疗的疗效,但严格的治疗时间窗限制,却使临床上大多数病人不能从中受益,症状性出血成为急性缺血性脑卒中溶栓治疗应用的最大障碍。
PROACT临床试验证实动脉内溶栓治疗对于改善预后有效,并且在血管再通方面有优势,但出血和再通血管的闭塞仍然是主要问题。近年来,随着病理生理过程的进一步认识及药物学、血管内介入治疗技术的发展,血管内溶栓治疗日益受到重视,但仍存在许多不尽完善之处,包括材料的选择、治疗时间窗以及超选择血管内溶栓药物的选择、用量、速率等,都是亟待解决问题。人类缺血性卒中在病因、发病部位、临床表现上有很大变化,因此模拟临床疾病的发病过程,建立稳定、可靠、重复性好、费用低廉、方法简单,发病机制和病理生理类似于人类血栓栓塞性脑梗死,更适用于缺血性脑血管病治疗学及溶栓药物的评价的模型,一直是人们普遍关注的课题。近年来随着实验动物科学的不断发展,该领域的研究已取得了长足的进步。自体血栓栓塞和溶栓治疗模型的建立有利于进一步研究缺血性脑血管病的病理生理改变和治疗效果。脑血管造影、核磁共振弥散成像技术、神经功能缺陷评分和脑梗死体积在脑缺血和溶栓治疗模型中保证实验成功率和准确性,具有重要的作用。
血小板在急性缺血性脑病中扮演重要的角色,抗血小板聚集治疗是基本措施。对于血管再通后的再闭塞问题,通过抗血小板或抗凝治疗能够解决,但最佳药物的选择、剂量、用药时间和方式等问题一直存在争议。75%的脑血栓栓子是“白血栓”,即富含血小板和纤维蛋白。急性新鲜的血小板血栓(白色血栓)使用传统的抗凝药(肝素)和溶栓剂(尿激酶等)是无效的。在心血管领域已有大量的临床循证医学证据表明,GPⅡb/Ⅲa受体拮抗剂在急性冠脉综合征(ACS)和经皮冠状动脉介入治疗(PCI)抗栓中的疗效和安全性。血小板糖蛋白GPⅡb/Ⅲa受体拮抗剂是一类新型抗血小板聚集药物,它通过抑制纤维蛋白原(Fg)与GPⅡb/Ⅲa特异性结合,这是引起血小板聚集的最后共同通路,有效地阻止各种途径诱导的血小板聚集,从而达到最大程度的抗血小板作用。近年来,国外GPⅡb/Ⅲa受体拮抗剂已经单独或联合纤溶药物静脉注射用于急性脑缺血疾病改善溶栓治疗效果和防止血管再闭塞,减少溶栓并发症的的发生。临床试验研究证明GPⅡb/Ⅲa受体拮抗剂在急性缺血性卒中中使用无明显增加颅内出血的几率,甚至在心肺旁路手术中使用替罗非班都是安全的。
溶栓不可避免的要激活凝血系统,导致缺血性脑卒中溶栓病人血栓再形成,使脑组织灌注不完全或延迟再灌注,微循环功能紊乱,甚至血管再通后闭塞,出现神经功能恶化。有研究发现替罗非班可以抑制微循环血栓形成,减少溶栓后组织无复流现象的发生。在急性大脑中阻塞病人中rtPA联合替罗非班静脉输注可使68%病人阻塞的大脑中动脉再通,随访脑组织缺血性损伤明显减小,神经功能明显改善,症状性出血率大约7%-8%。替罗非班已经常规用于尿激酶动脉内溶栓和机械性取栓的辅助治疗。
早期的一项研究使用阿昔单抗,肝素和阿司匹林治疗心肌梗死病人,发现能提高梗塞血管的血流。推测GPⅡb/Ⅲa受体拮抗剂通过使聚集的血小板解聚,改变了血栓的结构,使血栓发生了内源性的溶栓过程。
在脑血管病血管内介入治疗过程中血栓栓塞的发生率为3-10%,永久性神经功能损伤的发生率为3-5%。在这类病人溶栓是一个棘手的难题,尤其是在出血性疾病,例如颅内动脉瘤破裂的病人。替罗非班是非肽类小分子,特异性强,生物半衰期短,反复使用不易发生免疫反应。并且其起效快,给药后5分钟对血小板的抑制作用可达96%,停药后4小时内作用消失,血小板功能恢复。Li ebeskind DS等曾静脉内单独使用替罗非班成功治疗一例椎基底动脉急性栓塞rtPA溶栓效果不理想的病人。韩国医生Tae Jin Song在颈内动脉狭窄放置支架后因血栓形成引起颈动脉再阻塞,使用纤溶药物效果不理想,动脉内注射替罗非班后很快血栓溶解,血管再通。最近,有病例报道在破裂或未破裂动脉瘤血管内介入治疗中发生急性缺血性并发症,动脉内超选择注射GPⅡb/Ⅲa受体拮抗剂取得满意效果。以上研究均支持替罗非班有抗血栓形成的功能,动脉内注射安全。动脉内注射替罗非班取得了令人鼓舞的效果,但仅是个案探索,需要进一步的证明效果和安全性。
脑源性神经营养因子(Brain-derived neurotrophic factor, BDNF)为生物体内天然的蛋白分子,具有防止神经元死亡功能的一种蛋白质,主要由神经元和神经胶质细胞产生,是神经营养因子家族的重要成员。研究表明,在脑损伤后,除了存在一种主动性的程序性细胞凋亡过程,在耐受细胞内还存在一种平行的主动性神经元存活过程,脑源性神经营养因子(BDNF)就参与了这种主动性神经元存活过程。动物实验研究表明BDNF反应性增强是机体早期神经元对缺血、缺氧的自我保护。脑缺血损伤时,BDNF在梗死灶周围的“半暗区”甚至远隔区域均有显著表达,梗死灶核心BDNF永久性降低；缺血后12h梗死灶边界的内侧BDNF免疫反应性暂时性升高。国内此类报道亦较不一致,但大多集中在12-24h为其表达高峰,48h开始下降,表明BDNF在神经元损伤修复与再生中起重要作用。如果我们针对脑组织局灶性缺血损伤后,早期采取积极有效措施,改善缺血区脑组织的血液循环,防止脑组织缺血区神经元继续变性坏死,提高内源性BDNF表达水平,对脑缺血损伤后神经元的保护有重要意义。
目前,缺血性脑病GPⅡb/Ⅲa受体拮抗剂基本是静脉用药,关于动脉内用药的效果、安全性,以及使用剂量,国内外鲜有报道。盐酸替罗非班作为一种高效、高选择性的GPⅡb/Ⅲa受体拮抗剂,作用机制新颖、临床疗效确切、安全性好,是一种极有发展前途的治疗药物。
本课题分二部分进行。第一部分为替罗非班联合尿激酶超选择动脉内溶栓的动物实验研究,实验分二步进行：实验一研究了血管内介入技术制作兔大脑中动脉闭塞模型的方法,并评价其技术上的可行性和稳定性；实验二研究了替罗非班联合尿激酶超选择动脉内溶栓治疗兔急性大脑中动脉栓塞的疗效和安全性。采用X线数字减影(DSA)观察动脉内超选择溶栓的血管再通率、核磁共振弥散成像观察相对表观弥散系数(rADC)、改良Bederson评分法观察神经功能缺损。24h后处死动物,经氯化—2,3,5—三苯基四氯唑染色,作光镜病理形态学检查。第二部分研究了替罗非班在临床溶栓治疗中的应用、疗效和安全性,试验分二部分进行：试验一研究了替罗非班联合尿激酶在应用电解弹微簧圈栓塞治疗破裂动脉瘤中并发急性血栓形成经血管内介入溶栓治疗的疗效和安全性；试验二研究了替罗非班联合尿激酶血管内介入治疗颅内静脉窦血栓形成的疗效和安全性。
实验研究一介入技术制作兔大脑中动脉闭塞模型的研究
目的建立一种家兔大脑中动脉闭塞动物模型并经影像学诊断证实,而后行动脉内超选择接触性溶栓治疗,并评价其技术上的可行性和稳定性。
方法用改良腰穿针穿刺并搔刮兔耳动脉内膜形成自体血栓,用眼科手术刀将其切为0.5mm×0.4mm大小备用。分离麻醉固定后的家兔股动脉,将微导管经股动脉插入,在数字减影血管造影(DSA)透射下插入颈内动脉,经微导管注射兔自体动脉血栓建立兔大脑中动脉闭塞模型。采用DSA观察脑血管阻塞情况、MRI观察脑梗死部位、范围、改良Bederson评分法观察神经功能缺损。24h后处死动物,光学显微镜与透射电了显微镜观察病理改变。
结果所有家兔成功建立大脑中动脉栓塞模型,脑梗死灶均位于同侧大脑半球,局限于顶叶皮质、皮层下及基底节区,栓塞后的动物均存活24h。24h处死时测量脑梗死体积占对侧大脑半球的(44.08±5.13)%。TCI检查造模前平均流速(Vm)与造模后2h Vm和造模后5h Vm之间均存在显著差异(P=0.000和P=0.000)。造模后2h和造模后5h之间Vm无显著差异(P=0.908)。TTC染色、病理及MRI检查均发现脑组织脑梗死病灶部位一致。
结论血管内介入技术制作兔大脑中动脉自体血栓栓塞模型具有创伤小、易存活、栓塞可靠、脑梗死体积适中的优点。具有良好的可重复性和可控性,可用于脑梗死的早期诊断及药物溶栓研究。
实验研究二兔急性大脑中动脉栓塞替罗非班联合尿激酶超选择动脉内溶栓的实验研究
目的探讨替罗非班联合尿激酶超选择性动脉内溶栓治疗急性大脑中动脉栓塞的疗效和安全性。
方法健康雄性成年日本大白兔60只,体重2.5-3.Okg,采用自体血栓栓塞大脑中动脉制成急性脑梗塞模型,随机分为替罗非班组(T组)、尿激酶组(UK组)、替罗非班+尿激酶组(T+UK组)和对照组(C组),共四组。每组又随即分为两组即A(10只)、B组(5只),T组：在脑缺血后2h通过颈内动脉内微导管,缓慢推入生理盐水30mL+替罗非班5u g/kg,30min内推完;UK组：在脑缺血后2h通过颈内动脉内微导管,缓慢推入生理盐水30mL+尿激酶20000U/kg,30min内推完；T+UK组：脑缺血后2h通过颈内动脉内微导管,生理盐水15mL+替罗非班3u g/kg及生理盐水15mL+尿激酶10000U/kg交替缓慢推入,30min内推完；CG组：脑缺血后2h经微导管缓慢推入生理盐水30mL,30min内推完。A组采用X线数字减影(DSA)观察动脉内超选择溶栓的血管再通率、核磁共振弥散成像(diffusion-weighted imaging, DWI)观察相对表观弥散系数(relative apparent diffusion coefficient, rADC)、改良Bederson评分法观察神经功能缺损。24h后处死动物,A组经氯化—2,3,5—三苯基四氯唑(TTC)染色测量脑梗死灶的体积,B组行光学显微镜、电子显微镜和脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)免疫组化病理学检查。
结果替罗非班+尿激酶组(T+UK组)血管再通率为90%,病理检查未见明显出血。替罗非班+尿激酶组(T+UK组)rADC值与对照组、替罗非班组和尿激酶组之间均存在显著差异(P=0.000,P=0.000和P=0.011)；神经功能缺损评分替罗非班+尿激酶组与对照组、替罗非班组和尿激酶组之间均存在显著差异(P=0.000,P=0.000和P=0.029)；脑梗死面积百分率替罗非班+尿激酶组与对照组、替罗非班组和尿激酶组之间均存在显著差异(P=0.000,P=0.029和P=0.002)。均优于尿激酶组(UK组)、替罗非班组(T组)和对照组(CG组)。免疫组化BDNF显示：替罗非班+尿激酶组(T+UK组)BDNF表达较对照组(C组)、替罗非班组(T组)尿激酶组(UK组)增加,差异具有统计学意义(P=0.000,P=0.000和P=0.001)。电镜结果显示替罗非班+尿激酶组(T+UK组)神经元核形态基本正常,线粒体轻度肿胀,嵴增大。替罗非班组(T组)、尿激酶组(UK组)均显示神经元变性,细胞器中度肿胀,线粒体中度肿胀,嵴增大,数目减少,个别线粒体嵴断裂、消失。对照组(C组)可见神经元核固缩、核染色质溶解,细胞结构消失。
结论早期使用替罗非班联合尿激酶对兔超早期脑缺血模型给予动脉内溶栓治疗,其疗效肯定、安全,能完全或部分恢复脑动脉再通,明显减少脑梗塞体积,改善微循环并减少脑出血的发生率,优于单纯尿激酶动脉内溶栓。
临床研究一颅内动脉急性血栓形成时替罗非班联合尿激酶超选择动脉内溶栓的临床研究
目的研究在颅内破裂动脉瘤行弹簧圈栓塞过程中并发血栓形成,应用替罗非斑联合尿激酶动脉内介入溶栓治疗的疗效和安全性。
方法2010年5月至2012年2月有12例颅内动脉瘤破裂患者行弹簧圈介入栓塞治疗过程中并发急性血栓形成,完成动脉瘤栓塞后。于血栓形成1小时内,在DSA监视下,12例患者均给予替罗非班联合尿激酶动脉内超选择溶栓,以及机械性碎栓治疗。每10min行造影观察血管溶通情况,直至血管完全或部分再通。
结果本组病人除1例为椎动脉系外,其余均为颈内动脉系统闭塞。溶栓后即刻完全再通9例,术后48h头颅CT无颅内出血,1例轻度神经功能障碍,其余无明显神经功能缺失；1例血管部分再通,少量斑块残留,术后24h头颅CT无颅内出血,有轻度神经功能障碍,恢复期因心肌梗死死亡；1例血管完全再通,术后立即头颅CT示右侧额叶脑出血,左侧肢体瘫痪,保守治疗3月症状改善后出院；1例大部分血管再通,术后24h头颅CT示脑梗塞、急性脑水肿,行去骨瓣减压,术后3月残留右侧肢体偏瘫。
结论颅内动脉急性血栓形成,甚至是破裂动脉瘤栓塞过程中急性血栓形成,替罗非班联合尿激酶超选择溶栓治疗是安全、有效的治疗手段。
临床研究二替罗非班联合尿激酶超选择静脉窦内溶栓的临床研究
目的探讨替罗非斑联合尿激酶超选择颅内静脉窦内溶栓的安全性和有效性。
方法对9例颅内静脉窦血栓形成患者行替罗非班联合尿激酶性超选择静脉窦内溶栓、机械性破栓治疗。
结果8例患者的症状、体征明显改善,其中头痛消失7例,1例症状改善,死亡1例；出院前8例患者测脑脊液压力正常,血管造影检查证实7例患者静脉窦主干通畅,皮层静脉和深静脉恢复正常;1例部分再通。
结论替罗非班联合尿激酶超选择颅内静脉窦内溶栓是安全、有效的治疗手段。
The conventional wisdom is that early thrombolytic therapy has mainly taken the time window of3hours or less, designed by occlusion of the artery recanalization to restore perfusion of the ischemic area, in order to save the surviving brain tissue vitality, improve patient prognosis. Indeed, intravenous administration of recombinant tissue plasminogen activator (rtPA) as a procedure for thrombolysis is currently the only FDA-approved medical therapy for treatment of patients with acute ischemic stroke. Though intravenous thrombolytic therapy for acute stroke is now generally accepted, it has also been challenged. At the same time it also brings some of thrombolytic-related issues, such as intracranial hemorrhage, reocclusion, ischemia-reperfusion injury and other complications. Intravenous thrombolytic therapy, partial or complete recanalization rate of the internal carotid artery10%, about25%of the middle cerebral artery. Hemorrhage and vascular reocclusion is the main reason to limit thrombolytic therapy. Symptomatic hemorrhage was seen in a higher incidence (6%) of patients and severe consequences of forcing medical workers to re-examine this approach. The results confirmed the efficacy of thrombolytic therapy of acute phase again, but strict treatment time window restrictions, while filling the clinically most patients can not benefit from symptomatic hemorrhage as the biggest obstacle to therapeutic applications in acute ischemic stroke thrombolysis.
PROACT clinical trials confirmed that intra-arterial thrombolytic therapy to improve prognosis and have an advantage in recanalization, but hemorrhage and reocclusion of vascular remains the major problem. In recent years, with the further understanding pathophysiology of acute cerebral ischemia, involved in the development of pharmacology and intervention radiation techniques, intervention thrombolytic managment have received increasing attention. But there are still many imperfect place need to be resolved instantly, including material selection, the treatment time window, and superselective intravascular thrombolysis drug selection, dosage, rate, etc. To establish the animal models resembling human embolic stroke is the foundation for researching the pathogenesis and therapeutic strategies about cerebral thrombosis. In recent years, along with the perpetual development of the experimental animal science, there has been made rapid progress in this field. The construction of autologogus embolic cerebral ischemia and thrombolytic therapy model may be helpful to make further study on the pathophysiologic changes and therapy improvements. DSA, MR-DWI, neurological deficit scores and TTC staining technique are successful and accurate in detecting cerebral arterial embolism, and play important roles.
Platelets play an important role in acute cerebral ischemia, anti-platelet aggregation therapy is the basic measure. For reocclusion after recanalization, antiplatelet or anticoagulant therapy can be solved, but the best choice of drugs, dosage, administration time and method has been controversial.75%of cerebral emboli is a "white thrombus", that is rich in platelets and fibrin. Acute fresh platelet thrombus (white thrombus) use of anticoagulant drugs (heparin) and thrombolytic agents (urokinase) is not valid. In the cardiovascular field, there are a lot of clinical evidence-based medicine demonstrate that the GPⅡb/Ⅲa receptor antagonists are effective and safe antithrombotic in acute coronary syndrome (ACS) and percutaneous coronary intervention therapy (PCI). Platelet glycoprotein (GPⅡb/Ⅲa) receptor antagonists are a class of new antiplatelet aggregation drugs through the inhibition specific binding of fibrinogen (Fg) and GPⅡb/Ⅲa, this is the final common pathway of platelet aggregation, effectively blocking all ways to induced platelet aggregation, so as to achieve the greatest degree of anti-platelet effect. In recent years, foreign GPⅡb/Ⅲa receptor antagonist is administered alone or in combination with fibrinolytic drugs intravenously for acute cerebral ischemia to improve thrombolytic efficacy, prevent vascular reocclusion, and to reduce the thrombolytic complications. Clinical trials have shown that the GPⅡb/Ⅲa receptor antagonist no significantly increased the risk of intracranial hemorrhage in acute ischemic stroke. Even in cardiopulmonary bypass surgery, the use of tirofiban is safe.
Thrombolysis is inevitable to activate the coagulation system, resulting in thrombosis reformed, incomplete brain tissue perfusion or delayed reperfusion, microcirculation disorders, and even vascular recanalization after occlusion, neurological deterioration. Studies have found that tirofiban can inhibit microcirculation thrombosis, reduce no-reflow phenomenon after thrombolysis. Intravenous Tirofiban with rt-PA enabled68%of patients with middle cerebral artery recanalization, follow-up brain tissue ischemic injury was significantly reduced, significantly improved neurological function, symptomatic hemorrhagic rate of about7%-8%in acute middle cerebral artery occlusion. Tirofiban has been used routinely in the adjuvant therapy of urokinase arterial thrombolysis and mechanical thrombectomy.
A early study of use of abciximab, heparin and aspirin in the treatment of myocardial infarction patients found to improve blood flow to the infarct vascular. Speculated that the GPⅡb/Ⅲa receptor antagonist change the structure of the thrombus and make thrombosis endogenous thrombolytic, through depolymerization of platelet aggregation.
In cerebrovascular disease, thromboembolism incidence of endovascular interventional management is3-10%, permanent neurological deficit is the incidence of3-5%. Thrombolysis in such patients is controversial, especially in hemorrhagic diseases, such as patients with ruptured intracranial aneurysms. Tirofiban is non-peptide small molecules, specific, short biological half-life, repeated use of less prone to immune response. And it takes effects rapidly, inhibits platelet aggregation up to96%after administered5minutes, platelet function recovery within4hours after discontinuation. Liebeskind DS, etc. had successfully treated a patient of vertebral basilar artery acute thrombosis with intravenous Tirofiban alone, which rt-PA thrombolysis was not satisfied. South Korean doctor Tae Jin Song found that thrombus was dissolved and vessel recanalized soon after intra-arterial Tirofiban, while the use of fibrinolytic drugs were not effective in carotid thrombosis restenosis after the internal carotid artery stenosis stents. Recently, it is reported cases obtained satisfactory results, which of superselective intra-arterial injection of GPⅡb/Ⅲa receptor antagonists, for acute ischemic complications during endovascular interventional treatment of rupture or rupture of the aneurysms. The above studies support the anti-thrombosis, intra-arterial injection safety of tirofiban. Intra-arterial injection of tirofiban achieved encouraging results, but the only case to explore, need further proof of the efficacy and safety.
Brain-derived neurotrophic factor (BDNF), a natural protein molecules in vivo, to prevent neuronal death, is mainly produced by neurons and glial cells, an important member of neurotrophic factor. Studies have shown that after brain injury, there is a parallel initiative neuronal survival process in the resistant cells, in addition to a proactive process of programmed cell apoptosis. Brain-derived neurotrophic factor is involved in this initiative neuronal survival process. Animal studies have shown that BDNF reactivity enhancement is neuron self-protection to early ischemia and hypoxia. In cerebral ischemic injury, BDNF in the penumbra surround of infracted region, even in distant region, had a significant expression, while the BDNF expression of infarct core permanently reduced. BDNF inside of infarct border increased immunoreactivity temporarily. Demostic such reports were inconsistent, but were mostly concentrated in the peak of12-24h for BDNF expression,48h began to decline, indicating that BDNF played an important role in neuronal injury repair and regeneration. If we focus on local cerebral ischemic injury, early to take effective measures to improve the blood circulation of the ischemic area of brain, to prevent cerebral ischemia neurons continue to degeneration and necrosis, to improve endogenous BDNF expression levels has an important significance in protection of neurons after cerebral ischemic injury.
At present, the GPⅡb/Ⅲa receptor antagonists in acute ischemic stroke is basically the intravenous injection, the effect on intra-arterial medication, safety, and dosage has been rarely reported at home and abroad. Tirofiban as an efficient, highly selective GPⅡb/Ⅲa receptor antagonist, a novel mechanism of action, clinical efficacy, safety, good, is a very promising therapy.
This paper includes two parts. Experimental study on Tirofiban combined Urokinase selective intra-arterial thrombolysis in the middle cerebral artery occlusion was studied in part one, which including2experients:In first experiment, a middle cerebral artery occlusion (MCAO) animal model in rabbits were established with intervention technique, to provide a new model for image diagnosis and superselective intra-arterial contacting thrombolytic treatment and evaluating the technique feasibility and stability. In second experiment, efficacy and safety of Tirofiban combined Urokinase selective intra-arterial thrombolysis in the rabbit MCAO model was investigated. The recanalized rate, relative-apparent diffusion coefficient (rADC) and the neurologic function deficit score were compared among them. After24h, the animals were sacrificed and brain tissues were stained by chlorination-2,3,5-triphenyl tetrachloro and given light microscopy morphological examination. Therapeutic effects and safety of Tirofiban combined Urokinase in clinic were studied in part two, which including2trials:In first experiment, efficacy and safety of intra-arterial Tirofiban combined Urokinase was investigated when thrombus was acutely formed during electrolytic coil embolization of ruptured aneurysms. In second trial, the efficacy and risk of interventional Tirofiban and Urokinase thrombolysis for cerebral venous sinus thrombosis was studied.
Objective:To establish a middle cerebral artery occlusion (MCAO) animal model in the rabbit with intervention technique, to be demonstrated by image diagnosis, given super-selective intra-arterial contacting thrombolytic treatment and evaluated the technique feasibility and stability.
Methods:Autologous blood clot was cut into a0.5mm×0.4mm size with ophthalmic scalpel, which formed by lumbar puncture needle aspiration and scraping the intima of the rabbit ear artery. The rabbit was anesthetized and fixed and the proximal femoral artery of the rabbit was exposed. A microcatheter had been introduced into the internal carotid artery (ICA) under the guidance of the DSA. The rabbit autogenous arterial thrombosis were injected through the microcatheter to established the rabbit brain a middle cerebral artery occlusion model. Observed the cerebral vascular obstruction and infarction by DSA and MRI, the modified Bederson scoring for observing the.neurological deficits. Animals were sacrificed after24hours and pathological changes were observed by a light microscope and transmission electron microscope.
Results:All the middle cerebral artery occlusion animal model were successful established, the animals survived24h after embolization. The position of the cerebral infarction was all located at the ipsilateral hemisphere, and the lesions situated in the parietal cortex, subcortex and basal nucleus. The mean infarction size at24h sacrifice was (44.08±5.13)%. There was statistically significant difference, mean velocity (Vm) of before MCAO compared with mean velocity (Vm) of MCAO2h later and5h later (P=0.000and P=0.000). There was no statistically significant difference between2h and5h MCAO model (P=0.908). Diffusion MRI, TTC stain and pathology showed infarction lesion site in the brain was consistent
Conclusion:The middle cerebral artery occlusion model (MCAO) established in rabbit by selectively intra-arterial autologous clot has the advantages of fewer Invasive, easyer survive, reliable embolization, appropriate infarct size. These study confirmed that MCAO model established with selectively intra-arterial autologus clots had a goog repeatablility and controllability, and can be used for early diagnosis of cerebral infarction and clinical thrombolysis study.
Objective:To explore the efficacy and safety of intra-arterial Tirofiban Combined Urokinase Selective Intra-arterial Thrombolysis in the Middle Cerebral Artery Occlusion.
Methods:The middle cerebral artery occlusion model (MCAO) was established by autologous clot in Japan male rabbits (n=60) were randomly assigned before performance into four groups. Each group was divided into two subgroups:subgroup A (n=10), subgroup B (n=5). Group Tirofiban (group T):animals received intra-arterial thrombolysis of tirofiban (5μg/kg) over a period of30min at2h after onset of MACO; Group Urokinase (group U):a intra-arterial infusion of Urokinase (20000U/kg) was given in animals over a period of30min at2h after onset of MACO; Group Tirofian+Urokinase (group T+UK):an infusion of Tirofian (3μg/kg) and Urokinase (10000U/kg) was given intra-arterially alternatively in animals over a period of30min at2h after onset of MACO; Group Control (group C):animals in group C only received an intra-arterial infusion of normal saline on the same condition. The recanalized rate, relative-apparent diffusion coefficient (rADC) and the neurologic function deficit score were compared among each subgroup A. Animals were sacrificed after24hours, the infarct volume was measured after TTC staining in10animals of each subgroup A. Pathological changes were observed by a light microscope, electron microscope and immunohistochemistry in each subgroup B.
Results:The repatency rate in T+U group was90%, no hemorrhagic pathological was found. There were statistically significant differences, group T+U respectively compared with group C, group T, group UK in rADC, the neurologic function deficit score and percentage of cerebral infarction area (P=0.000,P=0.000and P=0.011; P=0.000, P=0.000and P=0.029; P=0.000,P=0.029and P=0.002). T+UK was better than other three groups, could significantly reduce brain injury and ameliorates neurological performance. Immunohistochemistry confirmed that BDNF in T+U group increased compared with group C, T and UK. Results in statistically significant difference (P=0.000, P=0.000and P=0.001). The electron microscope showed a nomal morphology of neuro, mitochondria mild swelling, cristae increase in group T+U, as well as neuronal mild degeneration, cell moderate swelling, mitochondrial moderate swelling, cristae increase, reducing the number of mitochondrial and cristae disappeared individually in group T and group U. Nuclear fast reduction, nuclear chromatin dissolution and cell structure disappearance were demonstrated in group C.
Conclution:Intra-arterial combined tirofiban and urokinase thrombolysis in the rabbit middle cerebral artery occlusion model (MCAO) is better than intra-arterial single urokinase, which can promote reperfusion, decrease infarct volume, improve the microcirculation and reduce the intracerebral hemorrhage rate.
Objective:To evaluate the efficacy and risk of interventional trofiban and urokinase thrombolysis for complicated thromboembolism during embolization of ruptured intracranial aneurysms with micro coil.
Methods:12cases of ruptured intracranial aneurysms underwent acute thromboembolism during coil embolization, continued to complete aneurysms embolization from2010May to2011Februray in our hospital. Within1hour after thrombosis, all cases were given inventional Tirofiban and Urokinase thrombolysis combined with mechanical thrombus maceration under DSA surveillance. Angiogram was performed to assess vascular thrombolysis situation every10min, until the vascular complete or partial recanalization.
Results:All are internal carotid artery system except one case of vertebral artery system.9cases achieved complete vascular recanalization after thrombolysis as confirmed on DSA studies, with negative cranial CT imagine manifestations after24h, no neurological deficits. Partial recanalization and mild neurological dysfunction was gained in1case, without intracranial hemorrhage after24h head CT check, died of myocardial infarction in recovery.1case achieved completely vascular recanalization was found the right frontal lobe hemorrhage with immediate postoperative CT scan, and paralysis of the left limbs, received conservative treatment and discharged with mild paralysis3months later.1case obtained most partial recanalization, while24h postoperative cranial CT showed cerebral infarction and cerebral edema. The patient was given decompressive craniectomy and discharged with residual right limb hemiparesis3months later.
Conclusion:Intra-arterial Tirofiban and Urokinase thrombolysis is an effective and safe measure for complicated thrombosis duiring embolization of intracranial aneurysms with coil.
Objective:To evaluate the efficacy and risk of interventional trofiban and urokinase thrombolysis for intracranial venous sinus thrombosis.
Methods:9patients with intracranial venous sinus thrombosis were performed intravenous sinus urokinase and tirofiban thrombolysis combined with mechanical thrombus maceration from2009January to2011January.
Results:After thrombolysis, symptoms and signs of8patients improved obviously and headache disappeared in7of them, but with only mild degree in other1and1died.7patients among them achieved recanalization of sinuses completely as confirmed on postprocedural DSA studies taken prior to hospital discharge, as well as normal intracranial pressure. Only1achieved recanalization of sinuses partly.
Conclusion:Intravenous sinus urokinase and tirofiban thrombolysis is an effective and safe measure for potentially catastrophic intracranial dural sinus thrombosis.
PROACT临床试验证实动脉内溶栓治疗对于改善预后有效,并且在血管再通方面有优势,但出血和再通血管的闭塞仍然是主要问题。近年来,随着病理生理过程的进一步认识及药物学、血管内介入治疗技术的发展,血管内溶栓治疗日益受到重视,但仍存在许多不尽完善之处,包括材料的选择、治疗时间窗以及超选择血管内溶栓药物的选择、用量、速率等,都是亟待解决问题。人类缺血性卒中在病因、发病部位、临床表现上有很大变化,因此模拟临床疾病的发病过程,建立稳定、可靠、重复性好、费用低廉、方法简单,发病机制和病理生理类似于人类血栓栓塞性脑梗死,更适用于缺血性脑血管病治疗学及溶栓药物的评价的模型,一直是人们普遍关注的课题。近年来随着实验动物科学的不断发展,该领域的研究已取得了长足的进步。自体血栓栓塞和溶栓治疗模型的建立有利于进一步研究缺血性脑血管病的病理生理改变和治疗效果。脑血管造影、核磁共振弥散成像技术、神经功能缺陷评分和脑梗死体积在脑缺血和溶栓治疗模型中保证实验成功率和准确性,具有重要的作用。
血小板在急性缺血性脑病中扮演重要的角色,抗血小板聚集治疗是基本措施。对于血管再通后的再闭塞问题,通过抗血小板或抗凝治疗能够解决,但最佳药物的选择、剂量、用药时间和方式等问题一直存在争议。75%的脑血栓栓子是“白血栓”,即富含血小板和纤维蛋白。急性新鲜的血小板血栓(白色血栓)使用传统的抗凝药(肝素)和溶栓剂(尿激酶等)是无效的。在心血管领域已有大量的临床循证医学证据表明,GPⅡb/Ⅲa受体拮抗剂在急性冠脉综合征(ACS)和经皮冠状动脉介入治疗(PCI)抗栓中的疗效和安全性。血小板糖蛋白GPⅡb/Ⅲa受体拮抗剂是一类新型抗血小板聚集药物,它通过抑制纤维蛋白原(Fg)与GPⅡb/Ⅲa特异性结合,这是引起血小板聚集的最后共同通路,有效地阻止各种途径诱导的血小板聚集,从而达到最大程度的抗血小板作用。近年来,国外GPⅡb/Ⅲa受体拮抗剂已经单独或联合纤溶药物静脉注射用于急性脑缺血疾病改善溶栓治疗效果和防止血管再闭塞,减少溶栓并发症的的发生。临床试验研究证明GPⅡb/Ⅲa受体拮抗剂在急性缺血性卒中中使用无明显增加颅内出血的几率,甚至在心肺旁路手术中使用替罗非班都是安全的。
溶栓不可避免的要激活凝血系统,导致缺血性脑卒中溶栓病人血栓再形成,使脑组织灌注不完全或延迟再灌注,微循环功能紊乱,甚至血管再通后闭塞,出现神经功能恶化。有研究发现替罗非班可以抑制微循环血栓形成,减少溶栓后组织无复流现象的发生。在急性大脑中阻塞病人中rtPA联合替罗非班静脉输注可使68%病人阻塞的大脑中动脉再通,随访脑组织缺血性损伤明显减小,神经功能明显改善,症状性出血率大约7%-8%。替罗非班已经常规用于尿激酶动脉内溶栓和机械性取栓的辅助治疗。
早期的一项研究使用阿昔单抗,肝素和阿司匹林治疗心肌梗死病人,发现能提高梗塞血管的血流。推测GPⅡb/Ⅲa受体拮抗剂通过使聚集的血小板解聚,改变了血栓的结构,使血栓发生了内源性的溶栓过程。
在脑血管病血管内介入治疗过程中血栓栓塞的发生率为3-10%,永久性神经功能损伤的发生率为3-5%。在这类病人溶栓是一个棘手的难题,尤其是在出血性疾病,例如颅内动脉瘤破裂的病人。替罗非班是非肽类小分子,特异性强,生物半衰期短,反复使用不易发生免疫反应。并且其起效快,给药后5分钟对血小板的抑制作用可达96%,停药后4小时内作用消失,血小板功能恢复。Li ebeskind DS等曾静脉内单独使用替罗非班成功治疗一例椎基底动脉急性栓塞rtPA溶栓效果不理想的病人。韩国医生Tae Jin Song在颈内动脉狭窄放置支架后因血栓形成引起颈动脉再阻塞,使用纤溶药物效果不理想,动脉内注射替罗非班后很快血栓溶解,血管再通。最近,有病例报道在破裂或未破裂动脉瘤血管内介入治疗中发生急性缺血性并发症,动脉内超选择注射GPⅡb/Ⅲa受体拮抗剂取得满意效果。以上研究均支持替罗非班有抗血栓形成的功能,动脉内注射安全。动脉内注射替罗非班取得了令人鼓舞的效果,但仅是个案探索,需要进一步的证明效果和安全性。
脑源性神经营养因子(Brain-derived neurotrophic factor, BDNF)为生物体内天然的蛋白分子,具有防止神经元死亡功能的一种蛋白质,主要由神经元和神经胶质细胞产生,是神经营养因子家族的重要成员。研究表明,在脑损伤后,除了存在一种主动性的程序性细胞凋亡过程,在耐受细胞内还存在一种平行的主动性神经元存活过程,脑源性神经营养因子(BDNF)就参与了这种主动性神经元存活过程。动物实验研究表明BDNF反应性增强是机体早期神经元对缺血、缺氧的自我保护。脑缺血损伤时,BDNF在梗死灶周围的“半暗区”甚至远隔区域均有显著表达,梗死灶核心BDNF永久性降低；缺血后12h梗死灶边界的内侧BDNF免疫反应性暂时性升高。国内此类报道亦较不一致,但大多集中在12-24h为其表达高峰,48h开始下降,表明BDNF在神经元损伤修复与再生中起重要作用。如果我们针对脑组织局灶性缺血损伤后,早期采取积极有效措施,改善缺血区脑组织的血液循环,防止脑组织缺血区神经元继续变性坏死,提高内源性BDNF表达水平,对脑缺血损伤后神经元的保护有重要意义。
目前,缺血性脑病GPⅡb/Ⅲa受体拮抗剂基本是静脉用药,关于动脉内用药的效果、安全性,以及使用剂量,国内外鲜有报道。盐酸替罗非班作为一种高效、高选择性的GPⅡb/Ⅲa受体拮抗剂,作用机制新颖、临床疗效确切、安全性好,是一种极有发展前途的治疗药物。
本课题分二部分进行。第一部分为替罗非班联合尿激酶超选择动脉内溶栓的动物实验研究,实验分二步进行：实验一研究了血管内介入技术制作兔大脑中动脉闭塞模型的方法,并评价其技术上的可行性和稳定性；实验二研究了替罗非班联合尿激酶超选择动脉内溶栓治疗兔急性大脑中动脉栓塞的疗效和安全性。采用X线数字减影(DSA)观察动脉内超选择溶栓的血管再通率、核磁共振弥散成像观察相对表观弥散系数(rADC)、改良Bederson评分法观察神经功能缺损。24h后处死动物,经氯化—2,3,5—三苯基四氯唑染色,作光镜病理形态学检查。第二部分研究了替罗非班在临床溶栓治疗中的应用、疗效和安全性,试验分二部分进行：试验一研究了替罗非班联合尿激酶在应用电解弹微簧圈栓塞治疗破裂动脉瘤中并发急性血栓形成经血管内介入溶栓治疗的疗效和安全性；试验二研究了替罗非班联合尿激酶血管内介入治疗颅内静脉窦血栓形成的疗效和安全性。
实验研究一介入技术制作兔大脑中动脉闭塞模型的研究
目的建立一种家兔大脑中动脉闭塞动物模型并经影像学诊断证实,而后行动脉内超选择接触性溶栓治疗,并评价其技术上的可行性和稳定性。
方法用改良腰穿针穿刺并搔刮兔耳动脉内膜形成自体血栓,用眼科手术刀将其切为0.5mm×0.4mm大小备用。分离麻醉固定后的家兔股动脉,将微导管经股动脉插入,在数字减影血管造影(DSA)透射下插入颈内动脉,经微导管注射兔自体动脉血栓建立兔大脑中动脉闭塞模型。采用DSA观察脑血管阻塞情况、MRI观察脑梗死部位、范围、改良Bederson评分法观察神经功能缺损。24h后处死动物,光学显微镜与透射电了显微镜观察病理改变。
结果所有家兔成功建立大脑中动脉栓塞模型,脑梗死灶均位于同侧大脑半球,局限于顶叶皮质、皮层下及基底节区,栓塞后的动物均存活24h。24h处死时测量脑梗死体积占对侧大脑半球的(44.08±5.13)%。TCI检查造模前平均流速(Vm)与造模后2h Vm和造模后5h Vm之间均存在显著差异(P=0.000和P=0.000)。造模后2h和造模后5h之间Vm无显著差异(P=0.908)。TTC染色、病理及MRI检查均发现脑组织脑梗死病灶部位一致。
结论血管内介入技术制作兔大脑中动脉自体血栓栓塞模型具有创伤小、易存活、栓塞可靠、脑梗死体积适中的优点。具有良好的可重复性和可控性,可用于脑梗死的早期诊断及药物溶栓研究。
实验研究二兔急性大脑中动脉栓塞替罗非班联合尿激酶超选择动脉内溶栓的实验研究
目的探讨替罗非班联合尿激酶超选择性动脉内溶栓治疗急性大脑中动脉栓塞的疗效和安全性。
方法健康雄性成年日本大白兔60只,体重2.5-3.Okg,采用自体血栓栓塞大脑中动脉制成急性脑梗塞模型,随机分为替罗非班组(T组)、尿激酶组(UK组)、替罗非班+尿激酶组(T+UK组)和对照组(C组),共四组。每组又随即分为两组即A(10只)、B组(5只),T组：在脑缺血后2h通过颈内动脉内微导管,缓慢推入生理盐水30mL+替罗非班5u g/kg,30min内推完;UK组：在脑缺血后2h通过颈内动脉内微导管,缓慢推入生理盐水30mL+尿激酶20000U/kg,30min内推完；T+UK组：脑缺血后2h通过颈内动脉内微导管,生理盐水15mL+替罗非班3u g/kg及生理盐水15mL+尿激酶10000U/kg交替缓慢推入,30min内推完；CG组：脑缺血后2h经微导管缓慢推入生理盐水30mL,30min内推完。A组采用X线数字减影(DSA)观察动脉内超选择溶栓的血管再通率、核磁共振弥散成像(diffusion-weighted imaging, DWI)观察相对表观弥散系数(relative apparent diffusion coefficient, rADC)、改良Bederson评分法观察神经功能缺损。24h后处死动物,A组经氯化—2,3,5—三苯基四氯唑(TTC)染色测量脑梗死灶的体积,B组行光学显微镜、电子显微镜和脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)免疫组化病理学检查。
结果替罗非班+尿激酶组(T+UK组)血管再通率为90%,病理检查未见明显出血。替罗非班+尿激酶组(T+UK组)rADC值与对照组、替罗非班组和尿激酶组之间均存在显著差异(P=0.000,P=0.000和P=0.011)；神经功能缺损评分替罗非班+尿激酶组与对照组、替罗非班组和尿激酶组之间均存在显著差异(P=0.000,P=0.000和P=0.029)；脑梗死面积百分率替罗非班+尿激酶组与对照组、替罗非班组和尿激酶组之间均存在显著差异(P=0.000,P=0.029和P=0.002)。均优于尿激酶组(UK组)、替罗非班组(T组)和对照组(CG组)。免疫组化BDNF显示：替罗非班+尿激酶组(T+UK组)BDNF表达较对照组(C组)、替罗非班组(T组)尿激酶组(UK组)增加,差异具有统计学意义(P=0.000,P=0.000和P=0.001)。电镜结果显示替罗非班+尿激酶组(T+UK组)神经元核形态基本正常,线粒体轻度肿胀,嵴增大。替罗非班组(T组)、尿激酶组(UK组)均显示神经元变性,细胞器中度肿胀,线粒体中度肿胀,嵴增大,数目减少,个别线粒体嵴断裂、消失。对照组(C组)可见神经元核固缩、核染色质溶解,细胞结构消失。
结论早期使用替罗非班联合尿激酶对兔超早期脑缺血模型给予动脉内溶栓治疗,其疗效肯定、安全,能完全或部分恢复脑动脉再通,明显减少脑梗塞体积,改善微循环并减少脑出血的发生率,优于单纯尿激酶动脉内溶栓。
临床研究一颅内动脉急性血栓形成时替罗非班联合尿激酶超选择动脉内溶栓的临床研究
目的研究在颅内破裂动脉瘤行弹簧圈栓塞过程中并发血栓形成,应用替罗非斑联合尿激酶动脉内介入溶栓治疗的疗效和安全性。
方法2010年5月至2012年2月有12例颅内动脉瘤破裂患者行弹簧圈介入栓塞治疗过程中并发急性血栓形成,完成动脉瘤栓塞后。于血栓形成1小时内,在DSA监视下,12例患者均给予替罗非班联合尿激酶动脉内超选择溶栓,以及机械性碎栓治疗。每10min行造影观察血管溶通情况,直至血管完全或部分再通。
结果本组病人除1例为椎动脉系外,其余均为颈内动脉系统闭塞。溶栓后即刻完全再通9例,术后48h头颅CT无颅内出血,1例轻度神经功能障碍,其余无明显神经功能缺失；1例血管部分再通,少量斑块残留,术后24h头颅CT无颅内出血,有轻度神经功能障碍,恢复期因心肌梗死死亡；1例血管完全再通,术后立即头颅CT示右侧额叶脑出血,左侧肢体瘫痪,保守治疗3月症状改善后出院；1例大部分血管再通,术后24h头颅CT示脑梗塞、急性脑水肿,行去骨瓣减压,术后3月残留右侧肢体偏瘫。
结论颅内动脉急性血栓形成,甚至是破裂动脉瘤栓塞过程中急性血栓形成,替罗非班联合尿激酶超选择溶栓治疗是安全、有效的治疗手段。
临床研究二替罗非班联合尿激酶超选择静脉窦内溶栓的临床研究
目的探讨替罗非斑联合尿激酶超选择颅内静脉窦内溶栓的安全性和有效性。
方法对9例颅内静脉窦血栓形成患者行替罗非班联合尿激酶性超选择静脉窦内溶栓、机械性破栓治疗。
结果8例患者的症状、体征明显改善,其中头痛消失7例,1例症状改善,死亡1例；出院前8例患者测脑脊液压力正常,血管造影检查证实7例患者静脉窦主干通畅,皮层静脉和深静脉恢复正常;1例部分再通。
结论替罗非班联合尿激酶超选择颅内静脉窦内溶栓是安全、有效的治疗手段。
The conventional wisdom is that early thrombolytic therapy has mainly taken the time window of3hours or less, designed by occlusion of the artery recanalization to restore perfusion of the ischemic area, in order to save the surviving brain tissue vitality, improve patient prognosis. Indeed, intravenous administration of recombinant tissue plasminogen activator (rtPA) as a procedure for thrombolysis is currently the only FDA-approved medical therapy for treatment of patients with acute ischemic stroke. Though intravenous thrombolytic therapy for acute stroke is now generally accepted, it has also been challenged. At the same time it also brings some of thrombolytic-related issues, such as intracranial hemorrhage, reocclusion, ischemia-reperfusion injury and other complications. Intravenous thrombolytic therapy, partial or complete recanalization rate of the internal carotid artery10%, about25%of the middle cerebral artery. Hemorrhage and vascular reocclusion is the main reason to limit thrombolytic therapy. Symptomatic hemorrhage was seen in a higher incidence (6%) of patients and severe consequences of forcing medical workers to re-examine this approach. The results confirmed the efficacy of thrombolytic therapy of acute phase again, but strict treatment time window restrictions, while filling the clinically most patients can not benefit from symptomatic hemorrhage as the biggest obstacle to therapeutic applications in acute ischemic stroke thrombolysis.
PROACT clinical trials confirmed that intra-arterial thrombolytic therapy to improve prognosis and have an advantage in recanalization, but hemorrhage and reocclusion of vascular remains the major problem. In recent years, with the further understanding pathophysiology of acute cerebral ischemia, involved in the development of pharmacology and intervention radiation techniques, intervention thrombolytic managment have received increasing attention. But there are still many imperfect place need to be resolved instantly, including material selection, the treatment time window, and superselective intravascular thrombolysis drug selection, dosage, rate, etc. To establish the animal models resembling human embolic stroke is the foundation for researching the pathogenesis and therapeutic strategies about cerebral thrombosis. In recent years, along with the perpetual development of the experimental animal science, there has been made rapid progress in this field. The construction of autologogus embolic cerebral ischemia and thrombolytic therapy model may be helpful to make further study on the pathophysiologic changes and therapy improvements. DSA, MR-DWI, neurological deficit scores and TTC staining technique are successful and accurate in detecting cerebral arterial embolism, and play important roles.
Platelets play an important role in acute cerebral ischemia, anti-platelet aggregation therapy is the basic measure. For reocclusion after recanalization, antiplatelet or anticoagulant therapy can be solved, but the best choice of drugs, dosage, administration time and method has been controversial.75%of cerebral emboli is a "white thrombus", that is rich in platelets and fibrin. Acute fresh platelet thrombus (white thrombus) use of anticoagulant drugs (heparin) and thrombolytic agents (urokinase) is not valid. In the cardiovascular field, there are a lot of clinical evidence-based medicine demonstrate that the GPⅡb/Ⅲa receptor antagonists are effective and safe antithrombotic in acute coronary syndrome (ACS) and percutaneous coronary intervention therapy (PCI). Platelet glycoprotein (GPⅡb/Ⅲa) receptor antagonists are a class of new antiplatelet aggregation drugs through the inhibition specific binding of fibrinogen (Fg) and GPⅡb/Ⅲa, this is the final common pathway of platelet aggregation, effectively blocking all ways to induced platelet aggregation, so as to achieve the greatest degree of anti-platelet effect. In recent years, foreign GPⅡb/Ⅲa receptor antagonist is administered alone or in combination with fibrinolytic drugs intravenously for acute cerebral ischemia to improve thrombolytic efficacy, prevent vascular reocclusion, and to reduce the thrombolytic complications. Clinical trials have shown that the GPⅡb/Ⅲa receptor antagonist no significantly increased the risk of intracranial hemorrhage in acute ischemic stroke. Even in cardiopulmonary bypass surgery, the use of tirofiban is safe.
Thrombolysis is inevitable to activate the coagulation system, resulting in thrombosis reformed, incomplete brain tissue perfusion or delayed reperfusion, microcirculation disorders, and even vascular recanalization after occlusion, neurological deterioration. Studies have found that tirofiban can inhibit microcirculation thrombosis, reduce no-reflow phenomenon after thrombolysis. Intravenous Tirofiban with rt-PA enabled68%of patients with middle cerebral artery recanalization, follow-up brain tissue ischemic injury was significantly reduced, significantly improved neurological function, symptomatic hemorrhagic rate of about7%-8%in acute middle cerebral artery occlusion. Tirofiban has been used routinely in the adjuvant therapy of urokinase arterial thrombolysis and mechanical thrombectomy.
A early study of use of abciximab, heparin and aspirin in the treatment of myocardial infarction patients found to improve blood flow to the infarct vascular. Speculated that the GPⅡb/Ⅲa receptor antagonist change the structure of the thrombus and make thrombosis endogenous thrombolytic, through depolymerization of platelet aggregation.
In cerebrovascular disease, thromboembolism incidence of endovascular interventional management is3-10%, permanent neurological deficit is the incidence of3-5%. Thrombolysis in such patients is controversial, especially in hemorrhagic diseases, such as patients with ruptured intracranial aneurysms. Tirofiban is non-peptide small molecules, specific, short biological half-life, repeated use of less prone to immune response. And it takes effects rapidly, inhibits platelet aggregation up to96%after administered5minutes, platelet function recovery within4hours after discontinuation. Liebeskind DS, etc. had successfully treated a patient of vertebral basilar artery acute thrombosis with intravenous Tirofiban alone, which rt-PA thrombolysis was not satisfied. South Korean doctor Tae Jin Song found that thrombus was dissolved and vessel recanalized soon after intra-arterial Tirofiban, while the use of fibrinolytic drugs were not effective in carotid thrombosis restenosis after the internal carotid artery stenosis stents. Recently, it is reported cases obtained satisfactory results, which of superselective intra-arterial injection of GPⅡb/Ⅲa receptor antagonists, for acute ischemic complications during endovascular interventional treatment of rupture or rupture of the aneurysms. The above studies support the anti-thrombosis, intra-arterial injection safety of tirofiban. Intra-arterial injection of tirofiban achieved encouraging results, but the only case to explore, need further proof of the efficacy and safety.
Brain-derived neurotrophic factor (BDNF), a natural protein molecules in vivo, to prevent neuronal death, is mainly produced by neurons and glial cells, an important member of neurotrophic factor. Studies have shown that after brain injury, there is a parallel initiative neuronal survival process in the resistant cells, in addition to a proactive process of programmed cell apoptosis. Brain-derived neurotrophic factor is involved in this initiative neuronal survival process. Animal studies have shown that BDNF reactivity enhancement is neuron self-protection to early ischemia and hypoxia. In cerebral ischemic injury, BDNF in the penumbra surround of infracted region, even in distant region, had a significant expression, while the BDNF expression of infarct core permanently reduced. BDNF inside of infarct border increased immunoreactivity temporarily. Demostic such reports were inconsistent, but were mostly concentrated in the peak of12-24h for BDNF expression,48h began to decline, indicating that BDNF played an important role in neuronal injury repair and regeneration. If we focus on local cerebral ischemic injury, early to take effective measures to improve the blood circulation of the ischemic area of brain, to prevent cerebral ischemia neurons continue to degeneration and necrosis, to improve endogenous BDNF expression levels has an important significance in protection of neurons after cerebral ischemic injury.
At present, the GPⅡb/Ⅲa receptor antagonists in acute ischemic stroke is basically the intravenous injection, the effect on intra-arterial medication, safety, and dosage has been rarely reported at home and abroad. Tirofiban as an efficient, highly selective GPⅡb/Ⅲa receptor antagonist, a novel mechanism of action, clinical efficacy, safety, good, is a very promising therapy.
This paper includes two parts. Experimental study on Tirofiban combined Urokinase selective intra-arterial thrombolysis in the middle cerebral artery occlusion was studied in part one, which including2experients:In first experiment, a middle cerebral artery occlusion (MCAO) animal model in rabbits were established with intervention technique, to provide a new model for image diagnosis and superselective intra-arterial contacting thrombolytic treatment and evaluating the technique feasibility and stability. In second experiment, efficacy and safety of Tirofiban combined Urokinase selective intra-arterial thrombolysis in the rabbit MCAO model was investigated. The recanalized rate, relative-apparent diffusion coefficient (rADC) and the neurologic function deficit score were compared among them. After24h, the animals were sacrificed and brain tissues were stained by chlorination-2,3,5-triphenyl tetrachloro and given light microscopy morphological examination. Therapeutic effects and safety of Tirofiban combined Urokinase in clinic were studied in part two, which including2trials:In first experiment, efficacy and safety of intra-arterial Tirofiban combined Urokinase was investigated when thrombus was acutely formed during electrolytic coil embolization of ruptured aneurysms. In second trial, the efficacy and risk of interventional Tirofiban and Urokinase thrombolysis for cerebral venous sinus thrombosis was studied.
Objective:To establish a middle cerebral artery occlusion (MCAO) animal model in the rabbit with intervention technique, to be demonstrated by image diagnosis, given super-selective intra-arterial contacting thrombolytic treatment and evaluated the technique feasibility and stability.
Methods:Autologous blood clot was cut into a0.5mm×0.4mm size with ophthalmic scalpel, which formed by lumbar puncture needle aspiration and scraping the intima of the rabbit ear artery. The rabbit was anesthetized and fixed and the proximal femoral artery of the rabbit was exposed. A microcatheter had been introduced into the internal carotid artery (ICA) under the guidance of the DSA. The rabbit autogenous arterial thrombosis were injected through the microcatheter to established the rabbit brain a middle cerebral artery occlusion model. Observed the cerebral vascular obstruction and infarction by DSA and MRI, the modified Bederson scoring for observing the.neurological deficits. Animals were sacrificed after24hours and pathological changes were observed by a light microscope and transmission electron microscope.
Results:All the middle cerebral artery occlusion animal model were successful established, the animals survived24h after embolization. The position of the cerebral infarction was all located at the ipsilateral hemisphere, and the lesions situated in the parietal cortex, subcortex and basal nucleus. The mean infarction size at24h sacrifice was (44.08±5.13)%. There was statistically significant difference, mean velocity (Vm) of before MCAO compared with mean velocity (Vm) of MCAO2h later and5h later (P=0.000and P=0.000). There was no statistically significant difference between2h and5h MCAO model (P=0.908). Diffusion MRI, TTC stain and pathology showed infarction lesion site in the brain was consistent
Conclusion:The middle cerebral artery occlusion model (MCAO) established in rabbit by selectively intra-arterial autologous clot has the advantages of fewer Invasive, easyer survive, reliable embolization, appropriate infarct size. These study confirmed that MCAO model established with selectively intra-arterial autologus clots had a goog repeatablility and controllability, and can be used for early diagnosis of cerebral infarction and clinical thrombolysis study.
Objective:To explore the efficacy and safety of intra-arterial Tirofiban Combined Urokinase Selective Intra-arterial Thrombolysis in the Middle Cerebral Artery Occlusion.
Methods:The middle cerebral artery occlusion model (MCAO) was established by autologous clot in Japan male rabbits (n=60) were randomly assigned before performance into four groups. Each group was divided into two subgroups:subgroup A (n=10), subgroup B (n=5). Group Tirofiban (group T):animals received intra-arterial thrombolysis of tirofiban (5μg/kg) over a period of30min at2h after onset of MACO; Group Urokinase (group U):a intra-arterial infusion of Urokinase (20000U/kg) was given in animals over a period of30min at2h after onset of MACO; Group Tirofian+Urokinase (group T+UK):an infusion of Tirofian (3μg/kg) and Urokinase (10000U/kg) was given intra-arterially alternatively in animals over a period of30min at2h after onset of MACO; Group Control (group C):animals in group C only received an intra-arterial infusion of normal saline on the same condition. The recanalized rate, relative-apparent diffusion coefficient (rADC) and the neurologic function deficit score were compared among each subgroup A. Animals were sacrificed after24hours, the infarct volume was measured after TTC staining in10animals of each subgroup A. Pathological changes were observed by a light microscope, electron microscope and immunohistochemistry in each subgroup B.
Results:The repatency rate in T+U group was90%, no hemorrhagic pathological was found. There were statistically significant differences, group T+U respectively compared with group C, group T, group UK in rADC, the neurologic function deficit score and percentage of cerebral infarction area (P=0.000,P=0.000and P=0.011; P=0.000, P=0.000and P=0.029; P=0.000,P=0.029and P=0.002). T+UK was better than other three groups, could significantly reduce brain injury and ameliorates neurological performance. Immunohistochemistry confirmed that BDNF in T+U group increased compared with group C, T and UK. Results in statistically significant difference (P=0.000, P=0.000and P=0.001). The electron microscope showed a nomal morphology of neuro, mitochondria mild swelling, cristae increase in group T+U, as well as neuronal mild degeneration, cell moderate swelling, mitochondrial moderate swelling, cristae increase, reducing the number of mitochondrial and cristae disappeared individually in group T and group U. Nuclear fast reduction, nuclear chromatin dissolution and cell structure disappearance were demonstrated in group C.
Conclution:Intra-arterial combined tirofiban and urokinase thrombolysis in the rabbit middle cerebral artery occlusion model (MCAO) is better than intra-arterial single urokinase, which can promote reperfusion, decrease infarct volume, improve the microcirculation and reduce the intracerebral hemorrhage rate.
Objective:To evaluate the efficacy and risk of interventional trofiban and urokinase thrombolysis for complicated thromboembolism during embolization of ruptured intracranial aneurysms with micro coil.
Methods:12cases of ruptured intracranial aneurysms underwent acute thromboembolism during coil embolization, continued to complete aneurysms embolization from2010May to2011Februray in our hospital. Within1hour after thrombosis, all cases were given inventional Tirofiban and Urokinase thrombolysis combined with mechanical thrombus maceration under DSA surveillance. Angiogram was performed to assess vascular thrombolysis situation every10min, until the vascular complete or partial recanalization.
Results:All are internal carotid artery system except one case of vertebral artery system.9cases achieved complete vascular recanalization after thrombolysis as confirmed on DSA studies, with negative cranial CT imagine manifestations after24h, no neurological deficits. Partial recanalization and mild neurological dysfunction was gained in1case, without intracranial hemorrhage after24h head CT check, died of myocardial infarction in recovery.1case achieved completely vascular recanalization was found the right frontal lobe hemorrhage with immediate postoperative CT scan, and paralysis of the left limbs, received conservative treatment and discharged with mild paralysis3months later.1case obtained most partial recanalization, while24h postoperative cranial CT showed cerebral infarction and cerebral edema. The patient was given decompressive craniectomy and discharged with residual right limb hemiparesis3months later.
Conclusion:Intra-arterial Tirofiban and Urokinase thrombolysis is an effective and safe measure for complicated thrombosis duiring embolization of intracranial aneurysms with coil.
Objective:To evaluate the efficacy and risk of interventional trofiban and urokinase thrombolysis for intracranial venous sinus thrombosis.
Methods:9patients with intracranial venous sinus thrombosis were performed intravenous sinus urokinase and tirofiban thrombolysis combined with mechanical thrombus maceration from2009January to2011January.
Results:After thrombolysis, symptoms and signs of8patients improved obviously and headache disappeared in7of them, but with only mild degree in other1and1died.7patients among them achieved recanalization of sinuses completely as confirmed on postprocedural DSA studies taken prior to hospital discharge, as well as normal intracranial pressure. Only1achieved recanalization of sinuses partly.
Conclusion:Intravenous sinus urokinase and tirofiban thrombolysis is an effective and safe measure for potentially catastrophic intracranial dural sinus thrombosis.
引文
[1]Kudo M,Aoyama A,Ichimori S,et al.An animal model of cerebral infarction homologous blood clot rats [J]. Stroke,1982,13 (4):505-508.
[2]Durukan A, Tatlisumak T. A cute ischemic stroke:overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia [J]. Pharmacol Biochem Behav,2007,87:179-197.
[3]胡顶高,吴宣富,余力.兔局灶性脑梗死溶栓动物模型的建立[J].第一军医大学学报,2000,20(4)：324-326.
[4]郑永玲,胡长林.大鼠大脑中动脉血栓栓塞脑缺血模型的实验研究[J].神经损伤与功能重建,2009(4)1：25-27.
[5]刘增品,刘怀军.犬脑缺血模型的建立及动脉内溶栓的研究[J].河北医科大学学报,2007,28(2)：105-110.
[6]Zhang Z,Zhang RL,Jiang Q,et al. A new rat model of the thrombotic focal cerebral ischemia[J].J Cereb Blood Flow Metab,1997,17(2):123-135.
[7]Kashiwabara S,Kurokawa Y,Uede T,et al.Direct continuous observation of in situ thrombolysis in the cerebral embolic model of rabbits [J].No To Shinkei,1998,50(4):347-354.
[8]Overgaard K,Sereghy T.Pedersen H.et al.Neuroprotection with NBQX and thrombolysis with rt-PA in rat embolic stroke[J].Neurol Res,1993,15(5):334-339.
[9]周智鹏,邓燕贤,邱维加,等.猴局部脑缺血模型的建立及t-PA溶栓效果的评价[J].临床放射学杂志,2007,26(5)：500-503.
[10]秦智勇,陈衔城,张福林.猪急性脑栓塞动物模型[J].上海医科大学学报,1998,25(5)：374-376.
[11]秦智勇,陈衔城,马端,等.不同剂量重组葡激酶治疗幼猪急性脑梗死对凝血和纤溶功能的影响[J].中国急救医学,2002,22(1)：4-6.
[12]Victor J,Marder,Dennis J.et al.Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke[J]. Stroke,2006,37:2086-2093.
[13]Overgaard K,Sereghy T,Pedersen H,et al.Effect of delayed thrombolysis with rt-PA in a rat embolic stroke model[J] J Cereb Blood Flow Metab,1994,14:472-477.
[14]Benes V,Zabramski JM,Boston M,et al.Effect of intra-arterial antifibrinolytic agents on autologuembolic in the cerebral circulation of rabbits[J].Stroke,1990,21(110):1594-1599.
[15]Busch E,Kruger K,Hossmann KA.Improved model of thromboembolic stroke and rt-PA induced reperfusion in the rat [J].Brain Research,1997,778:16-24.
[16]Carter LP, Guthkelch AN, Orozco J, et al. Influence of tissue plasminogen activator and heparin on cerebral ischemia in a rabbit model [J]. Stroke,1992, 23 (6):883-8.
[17]Hamilton MG,Lee JS,Cuming PG,et al.A comparison of intra-arterial and intravenous tissue-type plasminogen activator on autologous arterial emboli in the cerebral circulation of rabbits. Stroke,1994,25:651-656.
[18]Benes V,Zabramski JM,Boston M,et al.Effect of intra-arterial tissue plasminoger activator and urokinase on autologous arterial emboli in the cerebral circulation of rabbits[J].Stroke,1990,21:1594-1599.
[19]Lee JS,Hamilton MG,Zzbraski JM,ct al.Variations in the anatomy of the rabbit cervical carotid artery[J]. Stroke,1994,25:501-503.
[20]杨冀萍,刘怀军.脑缺血模型制作过程中的质量控制[J].中国临床医学影像杂志,2009,05：356-358.
[21]黎红华,陈文军,崔敏,等.DWI及MRA在大面积脑梗死早期诊断中的价值.脑与神经疾病杂志,2007,15(3)：223-225.
[22]Sharma VK.Tsivgoulis G, Lao AY, Alexandrov AV:Role of transcranial Doppler ultrasonography in evaluation of patients with cerebrovascular disease.Curr Neurol Neurosci Rep 2007;7:8-20.
[1]王文化,赵冬,吴桂贤,刘军,姚丽,吴兆苏：北京市1984-1999年人群脑卒中发病率变化趋势分析,中华流行病学杂志2001年8月第22卷第4期,269-272.
[2]Schellinger PD, Fiebach JB, Mohr A,et al.Thrombolytic therapy for ischemic stroke -a review.Part I:intravenous thrombolysis [J].Crit Care Med,2001, 29:1812-1818.
[3]刘珍友.兔脑缺血再灌注磁共振弥散成像与病理对照研究[D].青岛大学硕士论文,2007：102-105.
[4]兰文婧.DWI、DTI及MRS在脑梗死中的诊断价值研究[D].吉林大学硕士论文,2007：214-216.
[5]赵香梅,高传玉,张宾,等.替罗非班对急性心肌梗死患者高水平血小板聚集率和预后的影响[J].中国实用医刊,2010,37(4)：145-148.
[6]Khalessi AA, Natarajan SK, Orion D, et al. Acute stroke intervention[J].JACC Cardiovasc Interv,2011,4(3):261-269.
[7]Chiti A, Pizzanelli C, Terni E,et al. A case of recurrent basilar artery occlusion successfully treated with repeated intravascular procedures[J].Neurologist, 2011,17(2):95-97.
[8]Hwang G, Oh CW, Bang JS, et al.Superficial temporal artery to middle cerebral artery bypass in acute ischemic stroke and stroke in progress[J].Neurosurgery, 2011,68(3):723-729.
[9]Amaral-Silva A, Pineiro S, Molina CA.Sonothrombolysis for the treatment of acute stroke:current concepts and future directions[J].Expert Rev Neurother, 2011,11(2):265-273.
[10]J. Eileen Bird, Mary R. Giancarli, Nick Allegretto, et al. Prediction of the therapeutic index of marketed anti-coagulants and anti-platelet agents by guinea pig models of thrombosis and hemostasis. Thrombosis Research (2008) 123, 146-158.
[11]Salvatore Mangiafico, Martino Cellerini, Patrizia Nencini, et al. Intravenous Glycoprotein Ⅱb/Ⅲa Inhibitor (Tirofiban) followed by Intra-Arterial Urokinase and Mechanical Thrombolysis in Stroke. AJNR Am J Neuroradiol 2005;26:2595-2601.
[12]Deshmukh, Vivek R, Fiorella, David J, Albuquerque, Felipe C, et al. Intra-arterial Thrombolysis for Acute Ischemic Stroke:Preliminary Experience with Platelet Glycoprotein Ⅱb/Ⅲa Inhibitors as Adjunctive Therapy. Neurosurgery 2005;56(1):46-55.
[13]Straub, S; Junghans, U; Jovanovic, V; Wittsack, HJ; Seitz, RJ; Siebler, M. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke.2004,35(3):705-709.
[14]Mangiafico S, Cellerini M, Nencini P, Gensini G, Inzitari D. Intravenous glycoprotein Ⅱb/Ⅲa inhibitor (tirofiban) followed by intra-arterial urokinase and mechanical thrombolysis in stroke. AJNR Am J Neuroradiol 2005;26:2595-601.
[15]Shuaib A, Yang Y, Nakada MT, et al. Glycoprotein Ⅱb/Ⅲa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia:evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab 2002; 22:215-22.
[16]Chen MH, Wu SL, Lo MC, et al.Basilar artery occlusion in a teenaged boy treated with intra-arterial thrombolysis[J].Acta Neurol Taiwan, 2010,19(4):281-286.
[17]Harry J. Cloft, Owen B. Samuels, Frank C. Tong, and Jacques E. Dion. Use of Abciximab for Mediation of Thromboembolic Complications of Endovascular Therapy. AJNR Am J Neuroradiol 22:1764-1767.
[18]Tae Jin Song, Kee Oog Lee, Dong Joon Kim, and Kyung-Yul Lee. Rescue Treatment with Intra-arterial Tirofiban Infusion and Emergent Carotid Stenting. Yonsei Med J.2008.49(5):857-859.
[19]Ng PP, Phatouros CC, Khangure MS. Use of glycoprotein Ⅱb/Ⅲa inhibitor for a thromboembolic complication during Guglielmi detachable coil treatment of an acutely ruptured aneurysm. AJNR Am J Neuroradiol 2001;22:1761-1763.
[20]Joon K. Song, Yasunari Niimi, Patricia M. et al. Thrombus Formation during Intracranial Aneurysm Coil Placement:Treatment with Intra-Arterial Abciximab. AJNR Am J Neuroradiol2004; 25:1147-1153.
[21]Syfret DA, Mitchell P, Dowling R, et al.Does intra-arterial thrombolysis have a role as first-line intervention in acute ischaemic stroke[J] Intern Med J, 2011,41(3):220-226.
[22]杜敢琴,孙圣刚,马晓娟,等.血小板激活在氧化应激诱发小鼠短暂性脑缺血发作中的作用和替罗非班的干预作用.脑与神经疾病杂志,2008,16(4)：350-352.
[23]Seitz RJ, Meisel S, Moll M, Wittsack HJ, Junghans U, Siebler M. The effect of combined thrombolysis with rtPA and tirofiban on ischemic brain lesions. Neurology 2004;62:2110-2.
[24]Ding G, Jiang Q, Zhang L, et al. Analysis of combined treatment of embolic stroke in rat with r-tpa and a GPⅡB/Ⅲa inhibitor. J Cereb Blood Flow Metab 2005; 25:87-97.
[25]胡跃强,唐农,刘泰,等.大鼠局灶性脑缺血再灌注后BDNFmRNA及其蛋白的表达变化[J].中风与神经病杂志,2011(03)：220203.
[26]Ferrer I, Krup insli J, Goutan E, et al. Brain-derived neurotrophic factor reduces cortical cell death by ischemia after middle cerebral artery occlusion in the rat [J]. Acta Neuropatho,2001,101 (3):229-238.
[27]张三明,鲁翔BDNF在局部脑缺血大鼠的表达[J].江苏医药,2008,34(10)：10321033.
[28]江显萍,刘芳.糖尿病大鼠脑缺血再灌注脑组织BDNF表达及UPP阻断的影响[J].中国现代医生,2009,47(27)：01-03.
[1]Pelz DM, Lownie SP, Fox AJ. Thromboembolic events associated with the treatment of cerebral aneurysms with Guglielmi detachable coils. AJNR Am J Neuroradiol 1998; 19:1541-1547.
[2]冯晓峰,陈金春,黄建武,等.颅内动脉瘤栓塞治疗的并发症及处理[J].现代实用医学,2008,20(2),97-99.
[3]尹海燕,王苇,李澄,等.急性脑梗死动脉溶栓的现状、影像学评价与进展[J].国际医学放射学杂志,2011,34(1)：55-60.
[4]J. Eileen Bird, Mary R. Giancarli, Nick Allegretto, et al. Prediction of the therapeutic index of marketed anti-coagulants and anti-platelet agents by guinea pig models of thrombosis and hemostasis. Thrombosis Research (2008) 123, 146-158.
[5]Salvatore Mangiafico, Martino Cellerini, Patrizia Nencini, et al. Intravenous Glycoprotein Ⅱb/Ⅲa Inhibitor (Tirofiban) followed by Intra-Arterial Urokinase and Mechanical Thrombolysis in Stroke. AJNR Am J Neuroradiol 2005/26:2595-2601.
[6]Deshmukh, Vivek R, Fiorella, David J, Albuquerque, Felipe C, et al. Intra-arterial Thrombolysis for Acute Ischemic Stroke:Preliminary Experience with Platelet Glycoprotein Ⅱb/Ⅲa Inhibitors as Adjunctive Therapy. Neurosurgery 2005;56(1):46-55.
[7]Straub, S; Junghans, U; Jovanovic, V; Wittsack, HJ; Seitz, RJ; Siebler, M. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke.2004,35(3):705-709.
[8]Mangiafico S, Cellerini M, Nencini P, Gensini G, Inzitari D. Intravenous glycoprotein Ⅱb/Ⅲa inhibitor (tirofiban) followed by intra-arterial urokinase and mechanical thrombolysis in stroke. AJNR Am J Neuroradiol 2005;26:2595-601.
[9]Shuaib A, Yang Y, Nakada MT, et al. Glycoprotein Ⅱb/Ⅲa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia:evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab 2002; 22:215-22.
[10]Chen MH, Wu SL, Lo MC, et al.Basilar artery occlusion in a teenaged boy treated with intra-arterial thrombolysis[J].Acta Neurol Taiwan, 2010,19(4):281-286.
[11]Winkley JM, Adams HP. Potential role of abciximab in ischemic cerebrovascular disease. Am J Cardiol.2000; 85:47C-51C.
[12]Radke PW, Janssens U, Schwarz ER, vom Dahl J. Therapeutic dissolution of an intracoronary thrombus by prolonged intravenous platelet glycoprotein Ⅱb/Ⅲa antagonism. J Invasive Cardiol.1999; 11:679-681.
[13]Tae Jin Song, Kee Oog Lee, Dong Joon Kim, and Kyung-Yul Lee. Rescue Treatment with Intra-arterial Tirofiban Infusion and Emergent Carotid Stenting. Yonsei Med J.2008.49(5):857-859.
[14]Ng PP, Phatouros CC, Khangure MS. Use of glycoprotein Ⅱb/Ⅲa inhibitor for a thromboembolic complication during Guglielmi detachable coil treatment of an acutely ruptured aneurysm. AJNR Am J Neuroradiol 2001;22:1761-1763.
[15]Joon K. Song, Yasunari Niimi, Patricia M. et al. Thrombus Formation during Intracranial Aneurysm Coil Placement:Treatment with Intra-Arterial Abciximab. AJNR Am J Neuroradiol2004; 25:1147-1153.
[16]Harry J. Cloft, Owen B. Samuels, Frank C. Tong, and Jacques E. Dion. Use of Abciximab for Mediation of Thromboembolic Complications of Endovascular Therapy. AJNR Am J Neuroradiol 22:1764-1767.
[17]No author. Intra-arterial thrombolysis [J]. AJNR,2001,22(1):18-21.
[18]Kidwell CS, Saver JL, Carneado J, et al. Predictors of hemorrhagic transformation in patients receiving intra-arterial thrombolysis [J]. Stroke,2002, 33(3):717-724.
[19]Bourekas EC, Slivka AP, Shah R, et al. Intraarterial thrombolytic therapy within 3 hours of the onset of stroke [J]. Neurosurgery,2004,54(1):39-46.
[20]Califf RM. Combination therapy for acute myocardial infarction:fibrinolytic therapy and glycoprotein Ⅱb/Ⅲa inhibition. Am Heart J,2000,139(2 Pt 2): S33-S37.
[21]Qureshi AL, Siddiqui AM, Kim SH, et al. Reocclusion of recanalized arteries during intra-arterial thrombolysis for acute ischemic stroke. AJNR, 2004,25(2):322-328.
[22]Heo JH, Lee KY, Kim SH, et al. Immediate reocclusion following a successful thrombolysis in acute stroke:a pilot study. Neurology,2003,60(10):1684-1687.
[23]Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology,2002,59(6):862-867.
[24]Grotta JC, Welch KM, Fagan SC, et al. Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial. Stroke,2001,32(3):661-668.
[25]QIAO Qian-lin, ZHOU Shi, WANG Xue-jian, et al. Early reocclusion of the target vessel during intra-arterial thrombolysis for acute ischemic stroke. Chin J Interv Imaging Ther,2006,3(5):364-367.
[26]Lee KY, Heo JH, Lee SI, et al. Rescue treatment with abciximab in acute ischemic stroke. Neurology,2001,56 (11):1585-1587.
[27]Wu QH, Zhou S, Qian QL, et al. Intra-arterial thrombolysis in patients with acute ischemic stroke:choice of time window. Chin J Interv Imaging Ther (Chinese),2004,1(2):131-134
[1]王建祯,凌锋.颅内静脉窦血栓的溶栓治疗进展.山东医药,2007,47(15)：76-77.
[2]赵常坤,张全斌,许金明.重症颅内静脉窦血栓形成的血管内小剂量持续溶栓治疗.中风与神经疾病杂志,2010,27(2)：171-172.
[3]张强,李慎茂,吉训明,等.血管内介入治疗颅内静脉窦血栓形成.介入放射学杂志,2007,16(5)：303-306.
[4]黄捷,李旭东,王世波,等.颅内静脉窦血栓形成的治疗策略.当代医学,2009,15(29)：516-519.
[5]QIAO Qian-lin, ZHOU Shi, WANG Xue-jian, et al. Early reocclusion of the target vessel during intra-arterial thrombolysis for acute ischemic stroke. Chin J Interv Imaging Ther,2006,3(5):364-367.
[6]Harry J. Cloft, Owen B. Samuels, Frank C. Tong, and Jacques E. Dion. Use of Abciximab for Mediation of Thromboembolic Complications of Endovascular Therapy AJNR Am J Neuroradiol 22:1764-1767.
[7]Pitchaiah Mandava, Perumal Thiagarajan, Thomas A. Kent. Glycoprotein Ⅱb/Ⅲa Antagonists in Acute Ischaemic Stroke Current Status and Future Directions. Drugs 2008; 68 (8):1019-1028.
[8]Salvatore Mangiafico, Martino Cellerini, Patrizia Nencini, et al. Intravenous Glycoprotein Ⅱb/Ⅲa Inhibitor (Tirofiban) followed by Intra-Arterial Urokinase and Mechanical Thrombolysis in Stroke. AJNR Am J Neuroradiol 2005:26:2595-2601.
[9]Deshmukh, Vivek R, Fiorella, David J, Albuquerque, Felipe C, et al. Intra-arterial Thrombolysis for Acute Ischemic Stroke:Preliminary Experience with Platelet Glycoprotein Ⅱb/Ⅲa Inhibitors as Adjunctive Therapy. Neurosurgery 2005;56(1):46-55.
[1]王忠诚.神经外科学.第1版.武汉：湖北科学技术出版社,1998：667.
[2]Kudo M, Aoyama A, Ichimori S,et al. An Animal Model of Cerebral Infarction Homologous Blood Clot Rats[J]. Stroke (00399-2499),1982,13 (4):505-508.
[3]王文化,赵冬,吴桂贤,刘军,姚明,吴兆苏：北京市1984-1999年人群脑卒中发病率变化趋势分析,中华流行病学杂志2001年8月第22卷第4期,269-272.
[4]Theron J, Gourgheoux P, Casasco A, et al. Local intraarterial fibrinolysis in carotid territory [J]. AJNR,1989,10(4):753-761.
[5]Levine S.Anoxic-ischemic enceptalopathy in rats.Am J Pathol,1960,36:1-17.
[6]Robinson RG, Shoemaker WJ, Schlumpf M, et al. Effect of ezperimental cerebral infarction in rat on catecholamines and behaviour. Nature,1975,255:332-334.
[7]Watson BD, Dietrich WD, Busto R, et al. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol, 1985,17:497-504.
[8]曹霞,曹秉振.鼠须替代尼龙线栓塞大鼠大脑中动脉造成局灶性脑缺血模型研究[J].中国病理生理杂志,2001,17(4)：381-382.
[9]Tamura A, Graham DI, McCulloch J, et al. Focal cerebral ischaemia in the rat: description middle cerebral artery occlusion.[J]. Cereb Blood Flow Metab, 1981,1:53-60.
[10]Bribt S, Jacewicz M, Kiessling M, et al. Focal brain ischemia in the rat:Methods for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral common carotid arteries. [J]. Cereb Blood Flow METAB,1988,8:474-485.
[11]Hill NC, Millikan CH, Wakim KG, et al. Studies in Cerebrovascular Disease.Ⅶ Experimental Production of Cerebral Infarctions by Intracarotid Injection of Homologous Blood Clot. Preliminary Report [J]. Mayo Clin Proc (S0025 6196),1955,30:626-633.
[12]胡顶高,吴宣富,余力.兔局灶性脑梗死溶栓动物模型的建立[J].第一军医大学学报,2000,20：324-326.
[13]郑永玲,胡长林.大鼠大脑中动脉血栓栓塞脑缺血模型的实验研究[J].神经损伤与功能重建,2009.1.4.1：25-27.
[14]刘增品,刘怀军.犬脑缺血模型的建立及动脉内溶栓的研究[J]河北医科大学学报,2007,28,2：105-110.
[15]Zhang Z, Zhang RL Jiang Q,et al. A New rat Model of the Thrombotic Focal Cerebral Ischemia [J]. J Cereb Blood Flow Metab,1997,17(2):123-135.
[16]Kashiwabara S, Kurokawa Y, Uede T,et al. Direct continuous observation of in situ thrombolysis in the cerebral embolic model of rabbits [J].No To Shinkei,1998,50(4):347-354.
[17]Overgaard K, Sereghy T, Pedersen H, et al. Neuroprotection with NBQX and thrombolysis with rt-PA in rat embolic stroke [J].Neurol Res,1993,15(5):334-339.
[18]Sereghy T, Overgaard K, Boy sen G. Neuroprotection by Excitatory Amino Acid Antagonists Benefit of Thrombolysis in the Embolic Stroke in Rats [J]. Stroke (S0039-2499),1993,24:1702-1707.
[19]Overgaard K, Sereghy T, Pedersen H, et al. Effect of Delayed Thrombolysis with rt-PA in A Rat Embolic Stroke Model[J].J Cereb Blood Flow Metab (S0271-678X),1994,14:472-477.
[20]Benes V, Zabramski JM, Boston M,et al. Effect of Intra-arterial Antifibrinolytic Agents on Autologuembolic in the Cerebral Circulation of Rabbits[J]. Stroke (S0039-2499),1990,21(110):1594-1599.
[21]Busch E,Kruger K,Hossmann KA. Improved model of Thromboembolic Stroke and rt-PA Induced Reperfusion in the Rat [J]. Brain Research (S0006-8993),1997,778:16-24.
[22]Rebello S S, Driscoll E M,Lucchesi B R.TP-9021, a glycoprotein II b/IIIa platelet receptor antagonist prevents rethrombosis after successful arterial thrombolysis in the dog[J].Stroke,1997,28(9):1789-1796.
[23]刘小光,徐理钠.一种能评价溶栓和抗栓药的大鼠大脑中动脉血栓模型[J].药学学报,1995,30(9)：662-667.
[24]Tamura A, Graham DI, McCulloch J, et al. Focal Cerebral Ischaemia in the Rat: Description of Technique and Early Neuropathological Consequences Following Middle Cerebral Artery Occlusion [J]. J Cereb Blood Flow Metab (S0271 678X),1981,1(1):53-60.
[25]Bederson J B, Pitts L H, Tsuji M, et al Rat middle cerebral artery occlusion: Evaluation of the model and development of neurologic examination [J]. Stroke,1986,17:472-476.
[26]Marchhal G.Serrati C.Tiouc R,et al.PET imaging of cerebral perfusion and ocygen consumption in acute ischaemic stroke relation to outcome[J].Lanct,1993,341:295.
[27]LONGA E Z,WEINSTEIN P R,CARLSON S,et al.Reversible middle cerebral artery occlusion without craniectomy in rats [J].Stroke,1989,20(1):84-91.
[28]Demchuk A, Christou I,Wein T, et al:Accuracy and criteria for localizing arterial occlusion with transcranial Doppler. J Neuroimaging 2000;10:1-12.
[29]Demchuk A, Christou I,Wein T, et al:Specific transcranial Doppler flow findings related to the presence and site of arterial occlusion. Stroke 2000;31:140-146.
[30]Sliwka U,Rautenberg W:Multimodal ultrasound versus angiography for imaging the vertebrobasilar circulation. J Neuroimaging 1998;8:182.
[31]Sharma VK,Tsivgoulis G, Lao AY, Alexandrov AV:Role of transcranial Doppler ultrasonography in evaluation of patients with cerebrovascular disease.Curr Neurol Neurosci Rep 2007;7:8-20.
[32]Molina CA, Alexandrov AV:Transcranial Doppler ultrasound. In Caplan LR,Manning WJ(eds):Brain Embolism.New York:Informa Healthcare,2006,pp113-128.
[33]Alexandrov AV,Grotta JC:Arterial reocclusion in stroke patiens treated with intravenous tissue plasminogen activator.Neurology 2002;59:862-867.
[34]Rother J, Crpigny AJ, Arceuil H, et al. MR detection of cortical spreading depression immediately focal ischemia in the rat. JCereb Blood Metab,1996,47 (3):214-218.
[35]BUSZA A L, ALLEN K L, VAN BZUG GEN N, et al. Diffusion-weighted imaging studies of cerebral ischemia in gerbils [J]. Stroke,1992,23:1602-1612.
[36]黎红华,陈文军,崔敏,等.DWI及MRA在大面积脑梗死早期诊断中的价值.脑与神经疾病杂志,2007,15(3)：223-225.
[37]杨艳梅,冯晓源,崔梅,等.MRI对线栓法制作大鼠脑缺血再灌注模型分组的价值[J].临床放射学杂志,2007,26(9)：917-920.
[38]Resctepo L, Jacobs MA, Barker PB, et al. Etiology of perfusionand diffusion magnetic resonance imaging mismatch patterns. JNeuroimaging,2005,15(4): 254-260.
[39]Hoiss WD, Sobesky J, Hesselman V. Identifying thresholdspenumbra and irreversible tissue damage. Stroke,2004,35 (Suppl1):2671-2674.
[40]LI F,HAN S,TATLISUMAK T.A new method to improve in-bore middle cerebral artery occlusion in rats demonstration with diffusion-and perfusion-weighted imaging [J].Stroke,1998,29 (8):1715-1719.
[41]Tobias Neumana-Haefelin MD,Hans-Jorg Wittsack PhD.Frank Wenserski MD,et al.Diffusion- and perfusion-weighted MRI.(The DWI/PWI mismatch region in acute stroke [J].Stroke,1999,30(8):1591-1597.
[42]VOGEL I, MOBIUS C, KUSCHINSKY W. Early delineation of ischemic tissue in rat brain cryosections by high-contrast staining [J]. Stroke,1999,30 (5): 1134-1141.
[43]Alonso de LM, Diez TE, Carceller F, et al. Cerebral ischemia:from animal studies to clinical practice [J]. Cerebrovasc Dis,2001,11 (suppl 1):20.
[44]Lee JS, Hamilton MG, Zabramski JM. Variations in the anatomy of the rabbit cervical carotid artery [J]. Stroke,1994,25 (2):502.
[45]周智鹏,邓燕贤,邱维加,等.猴局部脑缺血模型的建立及t-PA溶栓效果的 评价[J].临床放射学杂志,2007,26(5)：500-503.
[46]秦智勇,陈衔城,张福林.猪急性脑栓塞动物模型[J].上海医科大学学报,1998,25(5)：374-376.
[47]秦智勇,陈衔城,马端,等.不同剂量重组葡激酶治疗幼猪急性脑梗死对凝血和纤溶功能的影响[J].中国急救医学,2002,22(1)：4-6.
[48]Burbridge B, Matte G, Remedios A. Complex intracranial arterial anatomy in swine is unsuitable for cerebral infarction projects [J]. Can Assoc Radiol J,2004, 55 (5):326.
[49]谢宁,段新芬,牛英才.线栓法制备大鼠大脑中动脉脑缺血动物模型影响因素探析[J].中医药管理杂志,2006,14(12)：51.
[50]MCLLVOY LH. The effect of hypothermia and hyperthermia on acute brain injury [J]. AACN Clin Issues,2005,16:488-500.
[51]GINSBERG M D, BUSTO R. Rodent models of cerebral ischemia [J]. Stroke, 1989,20:627-642
[1]Suwanwela NC, Phanthumchinda K, Likitjaroen Y. Thrombolytic therapy in acute ischemic stroke in Asia:The first prospective evaluation. Clin Neurol Neurosurg 2006;108:549-52.
[2]Peerlinck K, De Lepeleire I, Goldberg M, et al. MK-383(L-700462), a selective nonpeptide platelet glycoprotein Ⅱb/Ⅲa antagonist, it active in man [J]. Circulation,1993,88:1512-1517.
[3]Mc Clellan KJ, Goa KL. Tirofiban:a review of its use in acute coronary syndrome [J]. Drugs,1998,56:1067-1080.
[4]J. Eileen Bird, Mary R. Giancarli, Nick Allegretto, et al. Prediction of the therapeutic index of marketed anti-coagulants and anti-platelet agents by guinea pig models of thrombosis and hemostasis. Thrombosis Research (2008) 123, 146-158.
[5]Harker LA. Therapeutic inhibition of platelet function in stroke. Cerebrovasc Dis. 1998;8(suppl 5):8-18.
[6]The EPILOG Investigetors platelet glycoprotein Ⅱb/Ⅲa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med, 1997,336(24):1689-1696.
[7]Platelet receptor inhibition in ischemic syndrome management (PRJSM) study investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina [J]. N Engl J Med,1998,338:1498-1505.
[8]RESTORE Investigators. Effects of platelet glycoprotein Ⅱb/Ⅲa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty [J]. Circulation,1997,96: 1445-1453.
[9]Lincoff AM, Califf RM, Topol EJ. Platelet glycoproteins Ilb/IIIa receptor blockade in coronary artery disease. JACC,2000,35(5):1103-1115.
[10]Pancioli AM, Brott TG. Therapeutic potential of platelet glycoprotein Ⅱb/Ⅲa receptor antagonists in acute ischaemic stroke:scientific rationale and available evidence. CNS Drugs 2004; 18:981-8.
[11]秦华,梁先明.新型血小板GPⅡb/Ⅲa受体拮抗剂盐酸替罗非班,中国新药杂志,2002；11(3)：197-200.
[12]Busch E, Kruger K, Allegrini PR, et al. Reperfusion after thrombolytic therapy of embolic stroke in the rat:magnetic resonance and biochemical imaging [J]. J Cereb Blood Flow Metab,1998,18(4):407-418.
[13]The Abciximab in Ischemic Stroke Investigators. Abciximab in acute ischemic stroke:a randomized, double-blind, placebo-controlled, dose-escalation study. Stroke,2000,31(3):601-609.
[14]Junghans U, Seitz RJ, Aulich A, et al. Bleeding risk of tirofiban:A nonpeptide GPIIb/IIIa platelet receptor antagonist in progressive stroke:An open pilot study. Cerebrovasc Dis 2001;12:308-12.
[15]Straub S, Junghans U, Jovanovic V, et al. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke 2004; 35:705-709 Straub, S; Junghans, U; Jovanovic, V; Wittsack, HJ; Seitz, RJ; Siebler, M. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke.2004,35(3):705-709.
[16]Seitz RJ, Hanzavi M, Junghans U, et al. Thromblysis with recombinant tissue plasminogen activator and tirofiban in stroke:preliminary observations. Stroke, 2003,34(8):1932-1935.
[17]Haerten K, Krabbe C, Raiber M. Efficacy and safety of treatment of acute ischemic stroke with glycoprotein Ⅱb/Ⅲa receptor blocker in routine clinical practice. Dtsch Med Wochenschr,2004,129(12):607-610.
[18]Tamberella MR, Bhatt DL, Chew DP, et al. Relation of platelet inactivation with intravenous glycoprotein ⅱb/ⅲa antagonists to major bleeding (from The GOLD Study). Am J Cardiol 2002; 89:1429-31
[19]Alfonso Ciccone, Iosief Abraha, Ignazio Santilli. Glycoprotein Ⅱb/Ⅲa Inhibitors for Acute Ischemic Stroke. Stroke 2007;38;1113-1114
[20]Keaney JF, Jr, Larson MG, et al. Obesity and systemic oxidative stress clinical correlation of oxidative stress in the Framingham study. Arterioscler Thromb Vasc Biol,2003,23:434-439.
[21]杜敢琴,孙圣刚,马晓娟,等.血小板激活在氧化应激诱发小鼠短暂性脑缺血发作中的作用和替罗非班的干预作用.脑与神经疾病杂志,2008,16(4)：350-352.
[22]Choudhri TF, Hoh BL, Zerwes H-G, et al. Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP Ⅱb/Ⅲa receptor-mediated platelet aggregation. J Clin Invest 1998; 102:1301-10.
[23]Junghans U, Siebler M. Cerebral microembolism is blocked by tirofiban, a selective nonpeptide platelet glycoprotein Ⅱb/Ⅲa receptor antagonist. Circulation, 2003,107:2717-2721.
[24]Seitz RJ, Meisel S, Moll M, Wittsack HJ, Junghans U, Siebler M. The effect of combined thrombolysis with rtPA and tirofiban on ischemic brain lesions. Neurology 2004;62:2110-2.
[25]Ding G, Jiang Q, Zhang L, et al. Analysis of combined treatment of embolic stroke in rat with r-tpa and a GPⅡB/Ⅲa inhibitor. J Cereb Blood Flow Metab 2005; 25:87-97.
[26]Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology.2002;59:862-867.
[27]Leys D, Ringelstein EB, Kaste M, Hacke W. Facilities available in European hospitals treating stroke patients. Stroke 38(11),2985-2991 (2007).
[28]Alexandrov AV. Ultrasound identification and lysis of clots. Stroke 35(11 Suppl. 1),2722-2725(2004).
[29]Salvatore Mangiafico, Martino Cellerini, Patrizia Nencini, et al. Intravenous Glycoprotein Ⅱb/Ⅲa Inhibitor (Tirofiban) followed by Intra-Arterial Urokinase and Mechanical Thrombolysis in Stroke. AJNR Am J Neuroradiol 2005/26:2595-2601.
[30]Deshmukh, Vivek R, Fiorella, David J, Albuquerque, Felipe C, et al. Intra-arterial Thrombolysis for Acute Ischemic Stroke:Preliminary Experience with Platelet Glycoprotein Ⅱb/Ⅲa Inhibitors as Adjunctive Therapy. Neurosurgery 2005;56(1):46-55.
[31]Joseph J, Lynch JR, Jacquelynn JC, et al. Nonpeptide glycoprotein Ⅱb/Ⅲa inhibitors-antithrombotic effects of MK-0383 [J]. J Pharmacol Exp Ther, 1995,272(1):20-32.
[32]Mangiafico S, Cellerini M, Nencini P, Gensini G, Inzitari D. Intravenous glycoprotein Ⅱb/Ⅲa inhibitor (tirofiban) followed by intra-arterial urokinase and mechanical thrombolysis in stroke. AJNR Am J Neuroradiol 2005;26:2595-601.
[33]Victor J. Marder, Dennis J. Chute, Sidney Starkman, Anna M. Abolian, Chelsea Kidwell, David Liebeskind, Bruce Ovbiagele, Fernando Vinuela, Gary Duckwiler, Reza Jahan, Paul M. Vespa, Scott Selco, Venkatakrishna Rajajee, Doojin Kim, Nerses Sanossian and Jeffrey L. Saver. Analysis of Thrombi Retrieved From Cerebral Arteries of Patients With Acute Ischemic Stroke. Stroke. 2006;37;2086-2093.
[34]Moriguchi, A; Maeda, M; Mihara, K; Aoki, T; Matsuoka, N; Mutoh, S. FK419, a novel nonpeptide GPIIb/IIIa antagonist, restores microvascular patency and improves outcome in the guinea-pig middle cerebral artery thrombotic occlusion model:comparison with tirofiban. J Cereb Blood Flow Metab.2005,25(1):75-86.
[35]Gold HK, Garabedian HD, Dinsmore RE, et al. Restoration of 36. Mandava P, Kent TA. Intra-arterial therapies for acute ischemic coronary flow in myocardial infarction by intravenous chimeric 7E3 antibody without exogenous plasminogen activators:observations in animals and humans. Circulation 1997; 95:1755-9
[36]Shuaib A, Yang Y, Nakada MT, et al. Glycoprotein Ⅱb/Ⅲa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia:evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab 2002; 22:215-22.
[37]Liebeskind DS, Pollard JR, Schwartz ED, Cucchiara BL, McGarvey ML, Hurst RW. Vertebrobasilar thrombolysis with intravenous tirofiban:case report. J Thromb Thrombolysis.2002; 13:81-84.
[38]Pitchaiah Mandava, Perumal Thiagarajan, Thomas A. Kent. Glycoprotein Ⅱb/Ⅲa Antagonists in Acute Ischaemic Stroke Current Status and Future Directions. Drugs 2008; 68 (8):1019-1028.
[39]Harry J. Cloft, Owen B. Samuels, Frank C. Tong, and Jacques E. Dion. Use of Abciximab for Mediation of Thromboembolic Complications of Endovascular Therapy. AJNR Am J Neuroradiol 22:1764-1767
[40]Patrono C, Oller B, FitzGerald GA, et al. Platelet active drugs:the relationships among dose, effectiveness, and side effects:the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest,2004,126:234s-264.
[41]张宇晨,贾三庆,王雷,李虹伟,王永亮,王宇朋,赵林,姚道阔,丁荣晶.直接PCI术患者冠状动脉内注射替罗非班的安全性及其改善心肌灌注的研究.中国全科医学杂志,2007,10,22：34-36.
[42]Tae Jin Song, Kee Oog Lee, Dong Joon Kim, and Kyung-Yul Lee. Rescue Treatment with Intra-arterial Tirofiban Infusion and Emergent Carotid Stenting. Yonsei Med J.2008.49(5):857-859.
[43]Ng PP, Phatouros CC, Khangure MS. Use of glycoprotein Ⅱb-Ⅲa inhibitor for a thromboembolic complication during Guglielmi detachable coil treatment of an acutely ruptured aneurysm. AJNR Am J Neuroradiol 2001;22:1761-1763.
[44]Joon K. Song, Yasunari Niimi, Patricia M. et al. Thrombus Formation during Intracranial Aneurysm Coil Placement:Treatment with Intra-Arterial Abciximab. AJNR Am JNeuroradiol2004; 25:1147-1153.
[2]Durukan A, Tatlisumak T. A cute ischemic stroke:overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia [J]. Pharmacol Biochem Behav,2007,87:179-197.
[3]胡顶高,吴宣富,余力.兔局灶性脑梗死溶栓动物模型的建立[J].第一军医大学学报,2000,20(4)：324-326.
[4]郑永玲,胡长林.大鼠大脑中动脉血栓栓塞脑缺血模型的实验研究[J].神经损伤与功能重建,2009(4)1：25-27.
[5]刘增品,刘怀军.犬脑缺血模型的建立及动脉内溶栓的研究[J].河北医科大学学报,2007,28(2)：105-110.
[6]Zhang Z,Zhang RL,Jiang Q,et al. A new rat model of the thrombotic focal cerebral ischemia[J].J Cereb Blood Flow Metab,1997,17(2):123-135.
[7]Kashiwabara S,Kurokawa Y,Uede T,et al.Direct continuous observation of in situ thrombolysis in the cerebral embolic model of rabbits [J].No To Shinkei,1998,50(4):347-354.
[8]Overgaard K,Sereghy T.Pedersen H.et al.Neuroprotection with NBQX and thrombolysis with rt-PA in rat embolic stroke[J].Neurol Res,1993,15(5):334-339.
[9]周智鹏,邓燕贤,邱维加,等.猴局部脑缺血模型的建立及t-PA溶栓效果的评价[J].临床放射学杂志,2007,26(5)：500-503.
[10]秦智勇,陈衔城,张福林.猪急性脑栓塞动物模型[J].上海医科大学学报,1998,25(5)：374-376.
[11]秦智勇,陈衔城,马端,等.不同剂量重组葡激酶治疗幼猪急性脑梗死对凝血和纤溶功能的影响[J].中国急救医学,2002,22(1)：4-6.
[12]Victor J,Marder,Dennis J.et al.Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke[J]. Stroke,2006,37:2086-2093.
[13]Overgaard K,Sereghy T,Pedersen H,et al.Effect of delayed thrombolysis with rt-PA in a rat embolic stroke model[J] J Cereb Blood Flow Metab,1994,14:472-477.
[14]Benes V,Zabramski JM,Boston M,et al.Effect of intra-arterial antifibrinolytic agents on autologuembolic in the cerebral circulation of rabbits[J].Stroke,1990,21(110):1594-1599.
[15]Busch E,Kruger K,Hossmann KA.Improved model of thromboembolic stroke and rt-PA induced reperfusion in the rat [J].Brain Research,1997,778:16-24.
[16]Carter LP, Guthkelch AN, Orozco J, et al. Influence of tissue plasminogen activator and heparin on cerebral ischemia in a rabbit model [J]. Stroke,1992, 23 (6):883-8.
[17]Hamilton MG,Lee JS,Cuming PG,et al.A comparison of intra-arterial and intravenous tissue-type plasminogen activator on autologous arterial emboli in the cerebral circulation of rabbits. Stroke,1994,25:651-656.
[18]Benes V,Zabramski JM,Boston M,et al.Effect of intra-arterial tissue plasminoger activator and urokinase on autologous arterial emboli in the cerebral circulation of rabbits[J].Stroke,1990,21:1594-1599.
[19]Lee JS,Hamilton MG,Zzbraski JM,ct al.Variations in the anatomy of the rabbit cervical carotid artery[J]. Stroke,1994,25:501-503.
[20]杨冀萍,刘怀军.脑缺血模型制作过程中的质量控制[J].中国临床医学影像杂志,2009,05：356-358.
[21]黎红华,陈文军,崔敏,等.DWI及MRA在大面积脑梗死早期诊断中的价值.脑与神经疾病杂志,2007,15(3)：223-225.
[22]Sharma VK.Tsivgoulis G, Lao AY, Alexandrov AV:Role of transcranial Doppler ultrasonography in evaluation of patients with cerebrovascular disease.Curr Neurol Neurosci Rep 2007;7:8-20.
[1]王文化,赵冬,吴桂贤,刘军,姚丽,吴兆苏：北京市1984-1999年人群脑卒中发病率变化趋势分析,中华流行病学杂志2001年8月第22卷第4期,269-272.
[2]Schellinger PD, Fiebach JB, Mohr A,et al.Thrombolytic therapy for ischemic stroke -a review.Part I:intravenous thrombolysis [J].Crit Care Med,2001, 29:1812-1818.
[3]刘珍友.兔脑缺血再灌注磁共振弥散成像与病理对照研究[D].青岛大学硕士论文,2007：102-105.
[4]兰文婧.DWI、DTI及MRS在脑梗死中的诊断价值研究[D].吉林大学硕士论文,2007：214-216.
[5]赵香梅,高传玉,张宾,等.替罗非班对急性心肌梗死患者高水平血小板聚集率和预后的影响[J].中国实用医刊,2010,37(4)：145-148.
[6]Khalessi AA, Natarajan SK, Orion D, et al. Acute stroke intervention[J].JACC Cardiovasc Interv,2011,4(3):261-269.
[7]Chiti A, Pizzanelli C, Terni E,et al. A case of recurrent basilar artery occlusion successfully treated with repeated intravascular procedures[J].Neurologist, 2011,17(2):95-97.
[8]Hwang G, Oh CW, Bang JS, et al.Superficial temporal artery to middle cerebral artery bypass in acute ischemic stroke and stroke in progress[J].Neurosurgery, 2011,68(3):723-729.
[9]Amaral-Silva A, Pineiro S, Molina CA.Sonothrombolysis for the treatment of acute stroke:current concepts and future directions[J].Expert Rev Neurother, 2011,11(2):265-273.
[10]J. Eileen Bird, Mary R. Giancarli, Nick Allegretto, et al. Prediction of the therapeutic index of marketed anti-coagulants and anti-platelet agents by guinea pig models of thrombosis and hemostasis. Thrombosis Research (2008) 123, 146-158.
[11]Salvatore Mangiafico, Martino Cellerini, Patrizia Nencini, et al. Intravenous Glycoprotein Ⅱb/Ⅲa Inhibitor (Tirofiban) followed by Intra-Arterial Urokinase and Mechanical Thrombolysis in Stroke. AJNR Am J Neuroradiol 2005;26:2595-2601.
[12]Deshmukh, Vivek R, Fiorella, David J, Albuquerque, Felipe C, et al. Intra-arterial Thrombolysis for Acute Ischemic Stroke:Preliminary Experience with Platelet Glycoprotein Ⅱb/Ⅲa Inhibitors as Adjunctive Therapy. Neurosurgery 2005;56(1):46-55.
[13]Straub, S; Junghans, U; Jovanovic, V; Wittsack, HJ; Seitz, RJ; Siebler, M. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke.2004,35(3):705-709.
[14]Mangiafico S, Cellerini M, Nencini P, Gensini G, Inzitari D. Intravenous glycoprotein Ⅱb/Ⅲa inhibitor (tirofiban) followed by intra-arterial urokinase and mechanical thrombolysis in stroke. AJNR Am J Neuroradiol 2005;26:2595-601.
[15]Shuaib A, Yang Y, Nakada MT, et al. Glycoprotein Ⅱb/Ⅲa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia:evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab 2002; 22:215-22.
[16]Chen MH, Wu SL, Lo MC, et al.Basilar artery occlusion in a teenaged boy treated with intra-arterial thrombolysis[J].Acta Neurol Taiwan, 2010,19(4):281-286.
[17]Harry J. Cloft, Owen B. Samuels, Frank C. Tong, and Jacques E. Dion. Use of Abciximab for Mediation of Thromboembolic Complications of Endovascular Therapy. AJNR Am J Neuroradiol 22:1764-1767.
[18]Tae Jin Song, Kee Oog Lee, Dong Joon Kim, and Kyung-Yul Lee. Rescue Treatment with Intra-arterial Tirofiban Infusion and Emergent Carotid Stenting. Yonsei Med J.2008.49(5):857-859.
[19]Ng PP, Phatouros CC, Khangure MS. Use of glycoprotein Ⅱb/Ⅲa inhibitor for a thromboembolic complication during Guglielmi detachable coil treatment of an acutely ruptured aneurysm. AJNR Am J Neuroradiol 2001;22:1761-1763.
[20]Joon K. Song, Yasunari Niimi, Patricia M. et al. Thrombus Formation during Intracranial Aneurysm Coil Placement:Treatment with Intra-Arterial Abciximab. AJNR Am J Neuroradiol2004; 25:1147-1153.
[21]Syfret DA, Mitchell P, Dowling R, et al.Does intra-arterial thrombolysis have a role as first-line intervention in acute ischaemic stroke[J] Intern Med J, 2011,41(3):220-226.
[22]杜敢琴,孙圣刚,马晓娟,等.血小板激活在氧化应激诱发小鼠短暂性脑缺血发作中的作用和替罗非班的干预作用.脑与神经疾病杂志,2008,16(4)：350-352.
[23]Seitz RJ, Meisel S, Moll M, Wittsack HJ, Junghans U, Siebler M. The effect of combined thrombolysis with rtPA and tirofiban on ischemic brain lesions. Neurology 2004;62:2110-2.
[24]Ding G, Jiang Q, Zhang L, et al. Analysis of combined treatment of embolic stroke in rat with r-tpa and a GPⅡB/Ⅲa inhibitor. J Cereb Blood Flow Metab 2005; 25:87-97.
[25]胡跃强,唐农,刘泰,等.大鼠局灶性脑缺血再灌注后BDNFmRNA及其蛋白的表达变化[J].中风与神经病杂志,2011(03)：220203.
[26]Ferrer I, Krup insli J, Goutan E, et al. Brain-derived neurotrophic factor reduces cortical cell death by ischemia after middle cerebral artery occlusion in the rat [J]. Acta Neuropatho,2001,101 (3):229-238.
[27]张三明,鲁翔BDNF在局部脑缺血大鼠的表达[J].江苏医药,2008,34(10)：10321033.
[28]江显萍,刘芳.糖尿病大鼠脑缺血再灌注脑组织BDNF表达及UPP阻断的影响[J].中国现代医生,2009,47(27)：01-03.
[1]Pelz DM, Lownie SP, Fox AJ. Thromboembolic events associated with the treatment of cerebral aneurysms with Guglielmi detachable coils. AJNR Am J Neuroradiol 1998; 19:1541-1547.
[2]冯晓峰,陈金春,黄建武,等.颅内动脉瘤栓塞治疗的并发症及处理[J].现代实用医学,2008,20(2),97-99.
[3]尹海燕,王苇,李澄,等.急性脑梗死动脉溶栓的现状、影像学评价与进展[J].国际医学放射学杂志,2011,34(1)：55-60.
[4]J. Eileen Bird, Mary R. Giancarli, Nick Allegretto, et al. Prediction of the therapeutic index of marketed anti-coagulants and anti-platelet agents by guinea pig models of thrombosis and hemostasis. Thrombosis Research (2008) 123, 146-158.
[5]Salvatore Mangiafico, Martino Cellerini, Patrizia Nencini, et al. Intravenous Glycoprotein Ⅱb/Ⅲa Inhibitor (Tirofiban) followed by Intra-Arterial Urokinase and Mechanical Thrombolysis in Stroke. AJNR Am J Neuroradiol 2005/26:2595-2601.
[6]Deshmukh, Vivek R, Fiorella, David J, Albuquerque, Felipe C, et al. Intra-arterial Thrombolysis for Acute Ischemic Stroke:Preliminary Experience with Platelet Glycoprotein Ⅱb/Ⅲa Inhibitors as Adjunctive Therapy. Neurosurgery 2005;56(1):46-55.
[7]Straub, S; Junghans, U; Jovanovic, V; Wittsack, HJ; Seitz, RJ; Siebler, M. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke.2004,35(3):705-709.
[8]Mangiafico S, Cellerini M, Nencini P, Gensini G, Inzitari D. Intravenous glycoprotein Ⅱb/Ⅲa inhibitor (tirofiban) followed by intra-arterial urokinase and mechanical thrombolysis in stroke. AJNR Am J Neuroradiol 2005;26:2595-601.
[9]Shuaib A, Yang Y, Nakada MT, et al. Glycoprotein Ⅱb/Ⅲa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia:evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab 2002; 22:215-22.
[10]Chen MH, Wu SL, Lo MC, et al.Basilar artery occlusion in a teenaged boy treated with intra-arterial thrombolysis[J].Acta Neurol Taiwan, 2010,19(4):281-286.
[11]Winkley JM, Adams HP. Potential role of abciximab in ischemic cerebrovascular disease. Am J Cardiol.2000; 85:47C-51C.
[12]Radke PW, Janssens U, Schwarz ER, vom Dahl J. Therapeutic dissolution of an intracoronary thrombus by prolonged intravenous platelet glycoprotein Ⅱb/Ⅲa antagonism. J Invasive Cardiol.1999; 11:679-681.
[13]Tae Jin Song, Kee Oog Lee, Dong Joon Kim, and Kyung-Yul Lee. Rescue Treatment with Intra-arterial Tirofiban Infusion and Emergent Carotid Stenting. Yonsei Med J.2008.49(5):857-859.
[14]Ng PP, Phatouros CC, Khangure MS. Use of glycoprotein Ⅱb/Ⅲa inhibitor for a thromboembolic complication during Guglielmi detachable coil treatment of an acutely ruptured aneurysm. AJNR Am J Neuroradiol 2001;22:1761-1763.
[15]Joon K. Song, Yasunari Niimi, Patricia M. et al. Thrombus Formation during Intracranial Aneurysm Coil Placement:Treatment with Intra-Arterial Abciximab. AJNR Am J Neuroradiol2004; 25:1147-1153.
[16]Harry J. Cloft, Owen B. Samuels, Frank C. Tong, and Jacques E. Dion. Use of Abciximab for Mediation of Thromboembolic Complications of Endovascular Therapy. AJNR Am J Neuroradiol 22:1764-1767.
[17]No author. Intra-arterial thrombolysis [J]. AJNR,2001,22(1):18-21.
[18]Kidwell CS, Saver JL, Carneado J, et al. Predictors of hemorrhagic transformation in patients receiving intra-arterial thrombolysis [J]. Stroke,2002, 33(3):717-724.
[19]Bourekas EC, Slivka AP, Shah R, et al. Intraarterial thrombolytic therapy within 3 hours of the onset of stroke [J]. Neurosurgery,2004,54(1):39-46.
[20]Califf RM. Combination therapy for acute myocardial infarction:fibrinolytic therapy and glycoprotein Ⅱb/Ⅲa inhibition. Am Heart J,2000,139(2 Pt 2): S33-S37.
[21]Qureshi AL, Siddiqui AM, Kim SH, et al. Reocclusion of recanalized arteries during intra-arterial thrombolysis for acute ischemic stroke. AJNR, 2004,25(2):322-328.
[22]Heo JH, Lee KY, Kim SH, et al. Immediate reocclusion following a successful thrombolysis in acute stroke:a pilot study. Neurology,2003,60(10):1684-1687.
[23]Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology,2002,59(6):862-867.
[24]Grotta JC, Welch KM, Fagan SC, et al. Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial. Stroke,2001,32(3):661-668.
[25]QIAO Qian-lin, ZHOU Shi, WANG Xue-jian, et al. Early reocclusion of the target vessel during intra-arterial thrombolysis for acute ischemic stroke. Chin J Interv Imaging Ther,2006,3(5):364-367.
[26]Lee KY, Heo JH, Lee SI, et al. Rescue treatment with abciximab in acute ischemic stroke. Neurology,2001,56 (11):1585-1587.
[27]Wu QH, Zhou S, Qian QL, et al. Intra-arterial thrombolysis in patients with acute ischemic stroke:choice of time window. Chin J Interv Imaging Ther (Chinese),2004,1(2):131-134
[1]王建祯,凌锋.颅内静脉窦血栓的溶栓治疗进展.山东医药,2007,47(15)：76-77.
[2]赵常坤,张全斌,许金明.重症颅内静脉窦血栓形成的血管内小剂量持续溶栓治疗.中风与神经疾病杂志,2010,27(2)：171-172.
[3]张强,李慎茂,吉训明,等.血管内介入治疗颅内静脉窦血栓形成.介入放射学杂志,2007,16(5)：303-306.
[4]黄捷,李旭东,王世波,等.颅内静脉窦血栓形成的治疗策略.当代医学,2009,15(29)：516-519.
[5]QIAO Qian-lin, ZHOU Shi, WANG Xue-jian, et al. Early reocclusion of the target vessel during intra-arterial thrombolysis for acute ischemic stroke. Chin J Interv Imaging Ther,2006,3(5):364-367.
[6]Harry J. Cloft, Owen B. Samuels, Frank C. Tong, and Jacques E. Dion. Use of Abciximab for Mediation of Thromboembolic Complications of Endovascular Therapy AJNR Am J Neuroradiol 22:1764-1767.
[7]Pitchaiah Mandava, Perumal Thiagarajan, Thomas A. Kent. Glycoprotein Ⅱb/Ⅲa Antagonists in Acute Ischaemic Stroke Current Status and Future Directions. Drugs 2008; 68 (8):1019-1028.
[8]Salvatore Mangiafico, Martino Cellerini, Patrizia Nencini, et al. Intravenous Glycoprotein Ⅱb/Ⅲa Inhibitor (Tirofiban) followed by Intra-Arterial Urokinase and Mechanical Thrombolysis in Stroke. AJNR Am J Neuroradiol 2005:26:2595-2601.
[9]Deshmukh, Vivek R, Fiorella, David J, Albuquerque, Felipe C, et al. Intra-arterial Thrombolysis for Acute Ischemic Stroke:Preliminary Experience with Platelet Glycoprotein Ⅱb/Ⅲa Inhibitors as Adjunctive Therapy. Neurosurgery 2005;56(1):46-55.
[1]王忠诚.神经外科学.第1版.武汉：湖北科学技术出版社,1998：667.
[2]Kudo M, Aoyama A, Ichimori S,et al. An Animal Model of Cerebral Infarction Homologous Blood Clot Rats[J]. Stroke (00399-2499),1982,13 (4):505-508.
[3]王文化,赵冬,吴桂贤,刘军,姚明,吴兆苏：北京市1984-1999年人群脑卒中发病率变化趋势分析,中华流行病学杂志2001年8月第22卷第4期,269-272.
[4]Theron J, Gourgheoux P, Casasco A, et al. Local intraarterial fibrinolysis in carotid territory [J]. AJNR,1989,10(4):753-761.
[5]Levine S.Anoxic-ischemic enceptalopathy in rats.Am J Pathol,1960,36:1-17.
[6]Robinson RG, Shoemaker WJ, Schlumpf M, et al. Effect of ezperimental cerebral infarction in rat on catecholamines and behaviour. Nature,1975,255:332-334.
[7]Watson BD, Dietrich WD, Busto R, et al. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol, 1985,17:497-504.
[8]曹霞,曹秉振.鼠须替代尼龙线栓塞大鼠大脑中动脉造成局灶性脑缺血模型研究[J].中国病理生理杂志,2001,17(4)：381-382.
[9]Tamura A, Graham DI, McCulloch J, et al. Focal cerebral ischaemia in the rat: description middle cerebral artery occlusion.[J]. Cereb Blood Flow Metab, 1981,1:53-60.
[10]Bribt S, Jacewicz M, Kiessling M, et al. Focal brain ischemia in the rat:Methods for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral common carotid arteries. [J]. Cereb Blood Flow METAB,1988,8:474-485.
[11]Hill NC, Millikan CH, Wakim KG, et al. Studies in Cerebrovascular Disease.Ⅶ Experimental Production of Cerebral Infarctions by Intracarotid Injection of Homologous Blood Clot. Preliminary Report [J]. Mayo Clin Proc (S0025 6196),1955,30:626-633.
[12]胡顶高,吴宣富,余力.兔局灶性脑梗死溶栓动物模型的建立[J].第一军医大学学报,2000,20：324-326.
[13]郑永玲,胡长林.大鼠大脑中动脉血栓栓塞脑缺血模型的实验研究[J].神经损伤与功能重建,2009.1.4.1：25-27.
[14]刘增品,刘怀军.犬脑缺血模型的建立及动脉内溶栓的研究[J]河北医科大学学报,2007,28,2：105-110.
[15]Zhang Z, Zhang RL Jiang Q,et al. A New rat Model of the Thrombotic Focal Cerebral Ischemia [J]. J Cereb Blood Flow Metab,1997,17(2):123-135.
[16]Kashiwabara S, Kurokawa Y, Uede T,et al. Direct continuous observation of in situ thrombolysis in the cerebral embolic model of rabbits [J].No To Shinkei,1998,50(4):347-354.
[17]Overgaard K, Sereghy T, Pedersen H, et al. Neuroprotection with NBQX and thrombolysis with rt-PA in rat embolic stroke [J].Neurol Res,1993,15(5):334-339.
[18]Sereghy T, Overgaard K, Boy sen G. Neuroprotection by Excitatory Amino Acid Antagonists Benefit of Thrombolysis in the Embolic Stroke in Rats [J]. Stroke (S0039-2499),1993,24:1702-1707.
[19]Overgaard K, Sereghy T, Pedersen H, et al. Effect of Delayed Thrombolysis with rt-PA in A Rat Embolic Stroke Model[J].J Cereb Blood Flow Metab (S0271-678X),1994,14:472-477.
[20]Benes V, Zabramski JM, Boston M,et al. Effect of Intra-arterial Antifibrinolytic Agents on Autologuembolic in the Cerebral Circulation of Rabbits[J]. Stroke (S0039-2499),1990,21(110):1594-1599.
[21]Busch E,Kruger K,Hossmann KA. Improved model of Thromboembolic Stroke and rt-PA Induced Reperfusion in the Rat [J]. Brain Research (S0006-8993),1997,778:16-24.
[22]Rebello S S, Driscoll E M,Lucchesi B R.TP-9021, a glycoprotein II b/IIIa platelet receptor antagonist prevents rethrombosis after successful arterial thrombolysis in the dog[J].Stroke,1997,28(9):1789-1796.
[23]刘小光,徐理钠.一种能评价溶栓和抗栓药的大鼠大脑中动脉血栓模型[J].药学学报,1995,30(9)：662-667.
[24]Tamura A, Graham DI, McCulloch J, et al. Focal Cerebral Ischaemia in the Rat: Description of Technique and Early Neuropathological Consequences Following Middle Cerebral Artery Occlusion [J]. J Cereb Blood Flow Metab (S0271 678X),1981,1(1):53-60.
[25]Bederson J B, Pitts L H, Tsuji M, et al Rat middle cerebral artery occlusion: Evaluation of the model and development of neurologic examination [J]. Stroke,1986,17:472-476.
[26]Marchhal G.Serrati C.Tiouc R,et al.PET imaging of cerebral perfusion and ocygen consumption in acute ischaemic stroke relation to outcome[J].Lanct,1993,341:295.
[27]LONGA E Z,WEINSTEIN P R,CARLSON S,et al.Reversible middle cerebral artery occlusion without craniectomy in rats [J].Stroke,1989,20(1):84-91.
[28]Demchuk A, Christou I,Wein T, et al:Accuracy and criteria for localizing arterial occlusion with transcranial Doppler. J Neuroimaging 2000;10:1-12.
[29]Demchuk A, Christou I,Wein T, et al:Specific transcranial Doppler flow findings related to the presence and site of arterial occlusion. Stroke 2000;31:140-146.
[30]Sliwka U,Rautenberg W:Multimodal ultrasound versus angiography for imaging the vertebrobasilar circulation. J Neuroimaging 1998;8:182.
[31]Sharma VK,Tsivgoulis G, Lao AY, Alexandrov AV:Role of transcranial Doppler ultrasonography in evaluation of patients with cerebrovascular disease.Curr Neurol Neurosci Rep 2007;7:8-20.
[32]Molina CA, Alexandrov AV:Transcranial Doppler ultrasound. In Caplan LR,Manning WJ(eds):Brain Embolism.New York:Informa Healthcare,2006,pp113-128.
[33]Alexandrov AV,Grotta JC:Arterial reocclusion in stroke patiens treated with intravenous tissue plasminogen activator.Neurology 2002;59:862-867.
[34]Rother J, Crpigny AJ, Arceuil H, et al. MR detection of cortical spreading depression immediately focal ischemia in the rat. JCereb Blood Metab,1996,47 (3):214-218.
[35]BUSZA A L, ALLEN K L, VAN BZUG GEN N, et al. Diffusion-weighted imaging studies of cerebral ischemia in gerbils [J]. Stroke,1992,23:1602-1612.
[36]黎红华,陈文军,崔敏,等.DWI及MRA在大面积脑梗死早期诊断中的价值.脑与神经疾病杂志,2007,15(3)：223-225.
[37]杨艳梅,冯晓源,崔梅,等.MRI对线栓法制作大鼠脑缺血再灌注模型分组的价值[J].临床放射学杂志,2007,26(9)：917-920.
[38]Resctepo L, Jacobs MA, Barker PB, et al. Etiology of perfusionand diffusion magnetic resonance imaging mismatch patterns. JNeuroimaging,2005,15(4): 254-260.
[39]Hoiss WD, Sobesky J, Hesselman V. Identifying thresholdspenumbra and irreversible tissue damage. Stroke,2004,35 (Suppl1):2671-2674.
[40]LI F,HAN S,TATLISUMAK T.A new method to improve in-bore middle cerebral artery occlusion in rats demonstration with diffusion-and perfusion-weighted imaging [J].Stroke,1998,29 (8):1715-1719.
[41]Tobias Neumana-Haefelin MD,Hans-Jorg Wittsack PhD.Frank Wenserski MD,et al.Diffusion- and perfusion-weighted MRI.(The DWI/PWI mismatch region in acute stroke [J].Stroke,1999,30(8):1591-1597.
[42]VOGEL I, MOBIUS C, KUSCHINSKY W. Early delineation of ischemic tissue in rat brain cryosections by high-contrast staining [J]. Stroke,1999,30 (5): 1134-1141.
[43]Alonso de LM, Diez TE, Carceller F, et al. Cerebral ischemia:from animal studies to clinical practice [J]. Cerebrovasc Dis,2001,11 (suppl 1):20.
[44]Lee JS, Hamilton MG, Zabramski JM. Variations in the anatomy of the rabbit cervical carotid artery [J]. Stroke,1994,25 (2):502.
[45]周智鹏,邓燕贤,邱维加,等.猴局部脑缺血模型的建立及t-PA溶栓效果的 评价[J].临床放射学杂志,2007,26(5)：500-503.
[46]秦智勇,陈衔城,张福林.猪急性脑栓塞动物模型[J].上海医科大学学报,1998,25(5)：374-376.
[47]秦智勇,陈衔城,马端,等.不同剂量重组葡激酶治疗幼猪急性脑梗死对凝血和纤溶功能的影响[J].中国急救医学,2002,22(1)：4-6.
[48]Burbridge B, Matte G, Remedios A. Complex intracranial arterial anatomy in swine is unsuitable for cerebral infarction projects [J]. Can Assoc Radiol J,2004, 55 (5):326.
[49]谢宁,段新芬,牛英才.线栓法制备大鼠大脑中动脉脑缺血动物模型影响因素探析[J].中医药管理杂志,2006,14(12)：51.
[50]MCLLVOY LH. The effect of hypothermia and hyperthermia on acute brain injury [J]. AACN Clin Issues,2005,16:488-500.
[51]GINSBERG M D, BUSTO R. Rodent models of cerebral ischemia [J]. Stroke, 1989,20:627-642
[1]Suwanwela NC, Phanthumchinda K, Likitjaroen Y. Thrombolytic therapy in acute ischemic stroke in Asia:The first prospective evaluation. Clin Neurol Neurosurg 2006;108:549-52.
[2]Peerlinck K, De Lepeleire I, Goldberg M, et al. MK-383(L-700462), a selective nonpeptide platelet glycoprotein Ⅱb/Ⅲa antagonist, it active in man [J]. Circulation,1993,88:1512-1517.
[3]Mc Clellan KJ, Goa KL. Tirofiban:a review of its use in acute coronary syndrome [J]. Drugs,1998,56:1067-1080.
[4]J. Eileen Bird, Mary R. Giancarli, Nick Allegretto, et al. Prediction of the therapeutic index of marketed anti-coagulants and anti-platelet agents by guinea pig models of thrombosis and hemostasis. Thrombosis Research (2008) 123, 146-158.
[5]Harker LA. Therapeutic inhibition of platelet function in stroke. Cerebrovasc Dis. 1998;8(suppl 5):8-18.
[6]The EPILOG Investigetors platelet glycoprotein Ⅱb/Ⅲa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med, 1997,336(24):1689-1696.
[7]Platelet receptor inhibition in ischemic syndrome management (PRJSM) study investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina [J]. N Engl J Med,1998,338:1498-1505.
[8]RESTORE Investigators. Effects of platelet glycoprotein Ⅱb/Ⅲa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty [J]. Circulation,1997,96: 1445-1453.
[9]Lincoff AM, Califf RM, Topol EJ. Platelet glycoproteins Ilb/IIIa receptor blockade in coronary artery disease. JACC,2000,35(5):1103-1115.
[10]Pancioli AM, Brott TG. Therapeutic potential of platelet glycoprotein Ⅱb/Ⅲa receptor antagonists in acute ischaemic stroke:scientific rationale and available evidence. CNS Drugs 2004; 18:981-8.
[11]秦华,梁先明.新型血小板GPⅡb/Ⅲa受体拮抗剂盐酸替罗非班,中国新药杂志,2002；11(3)：197-200.
[12]Busch E, Kruger K, Allegrini PR, et al. Reperfusion after thrombolytic therapy of embolic stroke in the rat:magnetic resonance and biochemical imaging [J]. J Cereb Blood Flow Metab,1998,18(4):407-418.
[13]The Abciximab in Ischemic Stroke Investigators. Abciximab in acute ischemic stroke:a randomized, double-blind, placebo-controlled, dose-escalation study. Stroke,2000,31(3):601-609.
[14]Junghans U, Seitz RJ, Aulich A, et al. Bleeding risk of tirofiban:A nonpeptide GPIIb/IIIa platelet receptor antagonist in progressive stroke:An open pilot study. Cerebrovasc Dis 2001;12:308-12.
[15]Straub S, Junghans U, Jovanovic V, et al. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke 2004; 35:705-709 Straub, S; Junghans, U; Jovanovic, V; Wittsack, HJ; Seitz, RJ; Siebler, M. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke.2004,35(3):705-709.
[16]Seitz RJ, Hanzavi M, Junghans U, et al. Thromblysis with recombinant tissue plasminogen activator and tirofiban in stroke:preliminary observations. Stroke, 2003,34(8):1932-1935.
[17]Haerten K, Krabbe C, Raiber M. Efficacy and safety of treatment of acute ischemic stroke with glycoprotein Ⅱb/Ⅲa receptor blocker in routine clinical practice. Dtsch Med Wochenschr,2004,129(12):607-610.
[18]Tamberella MR, Bhatt DL, Chew DP, et al. Relation of platelet inactivation with intravenous glycoprotein ⅱb/ⅲa antagonists to major bleeding (from The GOLD Study). Am J Cardiol 2002; 89:1429-31
[19]Alfonso Ciccone, Iosief Abraha, Ignazio Santilli. Glycoprotein Ⅱb/Ⅲa Inhibitors for Acute Ischemic Stroke. Stroke 2007;38;1113-1114
[20]Keaney JF, Jr, Larson MG, et al. Obesity and systemic oxidative stress clinical correlation of oxidative stress in the Framingham study. Arterioscler Thromb Vasc Biol,2003,23:434-439.
[21]杜敢琴,孙圣刚,马晓娟,等.血小板激活在氧化应激诱发小鼠短暂性脑缺血发作中的作用和替罗非班的干预作用.脑与神经疾病杂志,2008,16(4)：350-352.
[22]Choudhri TF, Hoh BL, Zerwes H-G, et al. Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP Ⅱb/Ⅲa receptor-mediated platelet aggregation. J Clin Invest 1998; 102:1301-10.
[23]Junghans U, Siebler M. Cerebral microembolism is blocked by tirofiban, a selective nonpeptide platelet glycoprotein Ⅱb/Ⅲa receptor antagonist. Circulation, 2003,107:2717-2721.
[24]Seitz RJ, Meisel S, Moll M, Wittsack HJ, Junghans U, Siebler M. The effect of combined thrombolysis with rtPA and tirofiban on ischemic brain lesions. Neurology 2004;62:2110-2.
[25]Ding G, Jiang Q, Zhang L, et al. Analysis of combined treatment of embolic stroke in rat with r-tpa and a GPⅡB/Ⅲa inhibitor. J Cereb Blood Flow Metab 2005; 25:87-97.
[26]Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology.2002;59:862-867.
[27]Leys D, Ringelstein EB, Kaste M, Hacke W. Facilities available in European hospitals treating stroke patients. Stroke 38(11),2985-2991 (2007).
[28]Alexandrov AV. Ultrasound identification and lysis of clots. Stroke 35(11 Suppl. 1),2722-2725(2004).
[29]Salvatore Mangiafico, Martino Cellerini, Patrizia Nencini, et al. Intravenous Glycoprotein Ⅱb/Ⅲa Inhibitor (Tirofiban) followed by Intra-Arterial Urokinase and Mechanical Thrombolysis in Stroke. AJNR Am J Neuroradiol 2005/26:2595-2601.
[30]Deshmukh, Vivek R, Fiorella, David J, Albuquerque, Felipe C, et al. Intra-arterial Thrombolysis for Acute Ischemic Stroke:Preliminary Experience with Platelet Glycoprotein Ⅱb/Ⅲa Inhibitors as Adjunctive Therapy. Neurosurgery 2005;56(1):46-55.
[31]Joseph J, Lynch JR, Jacquelynn JC, et al. Nonpeptide glycoprotein Ⅱb/Ⅲa inhibitors-antithrombotic effects of MK-0383 [J]. J Pharmacol Exp Ther, 1995,272(1):20-32.
[32]Mangiafico S, Cellerini M, Nencini P, Gensini G, Inzitari D. Intravenous glycoprotein Ⅱb/Ⅲa inhibitor (tirofiban) followed by intra-arterial urokinase and mechanical thrombolysis in stroke. AJNR Am J Neuroradiol 2005;26:2595-601.
[33]Victor J. Marder, Dennis J. Chute, Sidney Starkman, Anna M. Abolian, Chelsea Kidwell, David Liebeskind, Bruce Ovbiagele, Fernando Vinuela, Gary Duckwiler, Reza Jahan, Paul M. Vespa, Scott Selco, Venkatakrishna Rajajee, Doojin Kim, Nerses Sanossian and Jeffrey L. Saver. Analysis of Thrombi Retrieved From Cerebral Arteries of Patients With Acute Ischemic Stroke. Stroke. 2006;37;2086-2093.
[34]Moriguchi, A; Maeda, M; Mihara, K; Aoki, T; Matsuoka, N; Mutoh, S. FK419, a novel nonpeptide GPIIb/IIIa antagonist, restores microvascular patency and improves outcome in the guinea-pig middle cerebral artery thrombotic occlusion model:comparison with tirofiban. J Cereb Blood Flow Metab.2005,25(1):75-86.
[35]Gold HK, Garabedian HD, Dinsmore RE, et al. Restoration of 36. Mandava P, Kent TA. Intra-arterial therapies for acute ischemic coronary flow in myocardial infarction by intravenous chimeric 7E3 antibody without exogenous plasminogen activators:observations in animals and humans. Circulation 1997; 95:1755-9
[36]Shuaib A, Yang Y, Nakada MT, et al. Glycoprotein Ⅱb/Ⅲa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia:evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab 2002; 22:215-22.
[37]Liebeskind DS, Pollard JR, Schwartz ED, Cucchiara BL, McGarvey ML, Hurst RW. Vertebrobasilar thrombolysis with intravenous tirofiban:case report. J Thromb Thrombolysis.2002; 13:81-84.
[38]Pitchaiah Mandava, Perumal Thiagarajan, Thomas A. Kent. Glycoprotein Ⅱb/Ⅲa Antagonists in Acute Ischaemic Stroke Current Status and Future Directions. Drugs 2008; 68 (8):1019-1028.
[39]Harry J. Cloft, Owen B. Samuels, Frank C. Tong, and Jacques E. Dion. Use of Abciximab for Mediation of Thromboembolic Complications of Endovascular Therapy. AJNR Am J Neuroradiol 22:1764-1767
[40]Patrono C, Oller B, FitzGerald GA, et al. Platelet active drugs:the relationships among dose, effectiveness, and side effects:the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest,2004,126:234s-264.
[41]张宇晨,贾三庆,王雷,李虹伟,王永亮,王宇朋,赵林,姚道阔,丁荣晶.直接PCI术患者冠状动脉内注射替罗非班的安全性及其改善心肌灌注的研究.中国全科医学杂志,2007,10,22：34-36.
[42]Tae Jin Song, Kee Oog Lee, Dong Joon Kim, and Kyung-Yul Lee. Rescue Treatment with Intra-arterial Tirofiban Infusion and Emergent Carotid Stenting. Yonsei Med J.2008.49(5):857-859.
[43]Ng PP, Phatouros CC, Khangure MS. Use of glycoprotein Ⅱb-Ⅲa inhibitor for a thromboembolic complication during Guglielmi detachable coil treatment of an acutely ruptured aneurysm. AJNR Am J Neuroradiol 2001;22:1761-1763.
[44]Joon K. Song, Yasunari Niimi, Patricia M. et al. Thrombus Formation during Intracranial Aneurysm Coil Placement:Treatment with Intra-Arterial Abciximab. AJNR Am JNeuroradiol2004; 25:1147-1153.