芬戈莫德联合阿替普酶治疗急性缺血性脑卒中探究性研究

发布时间：2018-04-19 00:14

本文选题：急性缺血性脑卒中 + 芬戈莫德　；参考：《天津医科大学》2016年博士论文

【摘要】：研究目的与内容:急性缺血性脑卒中(acute ischemic stroke,AIS)是最常见的脑卒中类型,具有高发病率、高致死率和高致残率的特点,严重危害患者的健康和生命。AIS后能否进行有效的治疗将直接影响患者的预后。目前对于发病3-4.5小时内的患者,重组组织型纤溶酶原激活剂-阿替普酶(Recombinant Tissue Plasminogen Activato-Alteplase,rt PA)作为目前唯一被循证医学证明有效治疗急性脑卒中的溶栓药物,在国内外已经得到广泛应用。然而阻塞的脑动脉再通后,不可避免会出现与rt PA相关的脑再灌注损伤,包括出血转化或占位性脑水肿等。出血性转化的发生机制可能与血管再通、再灌注损伤、侧支循环建立等有关。再灌注损伤往往减弱或抵消溶栓治疗所带来的益处,甚至会导致患者症状的加重。如何解决再灌注损伤问题成为rt PA治疗的关键。免疫炎症反应在AIS病理生理学中占具关键地位。免疫炎症信号参与了缺血后级联反应的的所有阶段。缺血性脑卒中4.5小时内应用rt PA溶栓治疗后,炎症是促进出血转化和血管源性水肿等再灌注损伤重要因素。芬戈莫德(Fingolimod,FTY720)作为鞘氨醇类似物作用于鞘氨醇-1-磷酸受体,在体内经磷酸化后与淋巴细胞表面的S1P受体结合,改变淋巴细胞的迁移,促使淋巴细胞进入淋巴组织,阻止其离开淋巴组织进入周围循环,进而防止这些免疫细胞浸润中枢神经系统(CNS),从而达到免疫抑制的效果。因此,我们假设抑制炎症反应可能将会是有利于急性脑卒中溶栓后再灌注损伤的治疗。前期的动物模型试验及临床验证性试验证明芬戈莫德作为新型免疫调节剂,可以明显减少脑梗死灶的扩大以及脑出血后血肿周围水肿,并对BBB通透性有保护作用,有效改善了患者的预后;然而,对于静脉阿替普酶溶栓治疗的AIS患者(首次发病4.5小时),芬戈莫德早期治疗的安全性和有效性尚不可知。本研究目的在于,阿替普酶静脉溶栓联合芬戈莫德治疗对AIS患者的近远期临床结果、主要终点和次要终点等方面的影响,并探讨其安全性。研究方法:我们对发病4.5h内AIS患者进行严格静脉溶栓及口服芬戈莫德适应征评估后,共筛选了47例患者进入本研究,其中阿替普酶治疗组25例作为对照组,阿替普酶联合芬戈莫德治疗组22例为实验组。实验组患者在静脉rt PA溶栓治疗前后,服用芬戈莫德(0.5mg/次,1次/天×3天)。治疗前后所有入组患者应用流式细胞学技术检测循环血淋巴细胞亚群变化(CD4+T,CD8+T,CD19+B和CD56+自然杀伤细胞),对患者神经功能进行NIHSS和m RS评分,通过治疗前后头MRI影像计算梗死体积变化、出血转化率及出血体积,以及观察是否存在不良事件情况,通过试验组与对照组比较是否存在统计学差异。论证通过阿替普酶联合芬戈莫德治疗,是否可以减少AIS患者出血转化及梗死体积,改善临床结果。研究结果:1.口服给予芬戈莫德0.5mg后24小时,联合治疗组患者循环血中CD4+T,CD8+T,CD19+B和CD56+自然杀伤细胞均有不同程度的稳定减少,并且这种下降趋势可以持续到第7天时。而90天时,循环血中这些淋巴细胞亚群均恢复到基线期水平。而对照组患者无淋巴细胞减少。2.阿替普酶静脉溶栓后,联合治疗组中14例(64%)患者存在不同程度的血管再通,对照组17例(68%)的患者闭塞的血管再通。血管再通率在两组之间没有差别(P=0.77)。3.溶栓治疗前后梗死体积变化:主要终点:静脉溶栓治疗1d后,与基线期比较,联合治疗组患者梗死体积增加量明显小于阿替普酶治疗组(10.1±1.2 vs34.3±10.4ml,P=0.035)。次要终点:溶栓治疗7d时,与基线期比较联合治疗组患者梗死体积明显减小,与阿替普酶治疗组比较有明显差异(-2.3±2.7 vs12.3±3.9ml,P=0.004),甚至小于基线期梗死体积。4.溶栓治疗后出血转化:主要终点:溶栓治疗1d时联合治疗组发生出血转化的例数少于阿替普酶组,8(36%):11(44%)。并且联合治疗组发生出血转化后出血体积明显小于阿替普酶治疗组(2.3±0.7 vs 4.5±1.2ml,P=0.012)。在出血转化程度方面,联合治疗组明显较阿替普酶治疗组轻。联合治疗组中出血转化均为出血性梗死,无脑实质出血患者。而阿替普酶治疗组中有36%患者的出血转化为脑实质血肿,影响了进一步脑梗死治疗。其中1例患者24小时内发生恶性大脑中动脉闭塞综合征。5.溶栓治疗前后神经功能评分变化:主要终点:溶栓治疗1d,联合治疗组患者临床功能改善好于阿替普酶治疗组,NIHSS分值为4(0-8)vs 2(2-8),P=0.021。次要终点:溶栓治疗7d,联合治疗组患者临床功能改善明显好于阿替普酶治疗组,NIHSS分值为2.5(0-7)vs 1(4-5),P=0.008。次要终点:随访90天时,联合治疗组神经功能缺损少于较阿替普酶治疗组,联合治疗组m RS分值中0-1分比例(73%)明显高于阿替普酶治疗组(32%),P=0.008。并且4-5分比例明显少于对照组,而2-3分比例两组大致相同。6.并发症和不良事件:两组患者中均未发生死亡、心肌梗死、脑梗死复发。阿替普酶组中有3例患者出现胃肠道出血,而联合治疗组中仅有1例发生了胃肠道出血。两组中均有5例患者发生高于38?C的发热。不良反应:两组患者发生不良事件例数分别是,阿替普酶组8(33),联合治疗组6(30)。均未发生因不良事件停药及严重不良事件。联合治疗组中疑似肺部感染率为14%和尿路感染率为9%;阿替普酶治疗组中两类感染分别为12%和8%,组间比较P值为1.00,无统计学差异。两组患者中均未发生其他常见或特殊不良事件。7.联合治疗组中患者未主诉胸部不适,未发现心律失常或房室传导阻滞。治疗前后血压、心率以及常规实验室检查无明显波动。研究结论芬戈莫德联合阿替普酶静脉溶栓治疗急性缺血性脑卒中24小时主要终点指标,包括梗死体积变化,出血转化以及临床结果改善方面,联合治疗优于单纯阿替普酶治疗。阿替普酶与芬戈莫德联合治疗的良好临床效应可能与保护血脑屏障及减少炎症反应有关。并且芬戈莫德治疗患者耐受性良好,无明显不良反应。本项研究的局限性在于小样本小,未选用最佳的随机化方法,缺乏平行对照组。缺血性脑卒中急性期应用芬戈莫德的安全性、免疫调节作用以及对中枢神经系统其他保护作用需要更大规模的临床试验进行研究评估。
[Abstract]:Objectives: acute ischemic stroke (acute ischemic, stroke, AIS) is the most common type of stroke, with high morbidity, high mortality and high morbidity characteristics, serious harm to the health and life of patients after.AIS treatment can effectively will directly affect the prognosis of patients. The incidence of 3-4.5 hours with recombinant tissue plasminogen activator alteplase (Recombinant Tissue Plasminogen Activato-Alteplase, RT PA) as the only evidence of thrombolytic drugs proved effective medicine for the treatment of acute stroke, has been widely used at home and abroad. However, the obstruction of cerebral artery recanalization, inevitably there will be again reperfusion injury associated with RT PA of the brain, including hemorrhagic transformation or occupying cerebral edema. Hemorrhagic transformation mechanism may be related to vascular recanalization and reperfusion injury, the establishment of collateral circulation Reperfusion injury and so on. Bring tend to reduce or offset the benefits of thrombolytic therapy, and even lead to the exacerbation of symptoms. How to solve the problem of reperfusion injury has become a key RT PA treatment. The immune inflammatory reaction in the pathophysiology of AIS takes a key position. All stages are involved in the inflammatory cascade reaction after cerebral ischemia the ischemic stroke within 4.5 hours of application of RT PA after thrombolytic therapy, the inflammation is an important factor in the promotion of hemorrhagic transformation and vasogenic edema, reperfusion injury. Fingolimod (Fingolimod, FTY720) as a function of sphingosine analogues to sphingosine -1- phosphate receptor binding in vivo by phosphorylation and cell surface receptor S1P change, migration of lymphocytes, promote lymphocytes into lymphoid tissue, prevent it from leaving lymphoid tissue into the surrounding circulation, thus preventing the infiltration of immune cells in the central nervous system. The system (CNS), so as to achieve the immunosuppressive effect. Therefore, we hypothesized that inhibiting the inflammatory reaction may be beneficial to treatment of acute stroke reperfusion injury after thrombolysis. The animal model test and clinical verification experiment proved that fingolimod as a new immunomodulator can significantly reduce infarct expansion and brain after intracerebral hemorrhage and edema, and has a protective effect on the permeability of BBB, effectively improve the prognosis of the patients; however, for intravenous thrombolysis with alteplase in patients with AIS (the first 4.5 hours of onset), the safety and effectiveness of Fingomo's early treatment is unknown. The purpose of this study is that alteplase intravenous thrombolysis combined with Finn Gomo de in the treatment of short and long term clinical results of AIS patients, the main effect of end point and secondary end point, and to discuss its safety. Methods: we study on the onset of 4.5H AI S patients were strictly intravenous thrombolytic therapy and oral fingolimod indications were selected after evaluation, 47 patients were enrolled in this study, the alteplase treatment group of 25 cases as control group, alteplase combined with fingolimod treatment group of 22 cases as experimental group. The patients in the experimental group RT PA intravenous thrombolysis before and after treatment, taking fingolimod (0.5mg/ time, 1 times / day x 3 days) before and after treatment. All the patients enrolled in the application of flow cytometric detection of circulating lymphocyte subsets (CD4+T, CD8+T, CD19+B and CD56+ natural killer cells), NIHSS and m RS score of neurological function in patients with treatment before and after the head MRI images to calculate the infarction volume changes, bleeding rate and bleeding into volume, and observe whether there is any adverse events, through the test group compared with the control group. There was significant difference demonstrated by alteplase combined with fingolimod treatment, whether can AIS patients with hemorrhagic transformation and reduce infarct volume and improve clinical outcomes. Results: 1. oral administration of fingolimod 0.5mg after 24 hours, the combined treatment of CD4+T patients, circulating CD8+T, CD19+B and CD56+ natural killer cells have different degrees of stability is reduced, and this decline can last up to seventh days and 90. These days, the circulation of blood lymphocyte subsets were restored to baseline level. While patients in the control group without.2. lymphocytes decreased alteplase for intravenous thrombolysis after combined treatment group in 14 cases (64%) patients had different degree of recanalization, 17 cases of the control group (68%) of the patients with occlusion of blood vessels pass. The recanalization rate did not differ between the two groups (P=0.77) changes of infarct volume before and after thrombolytic therapy of.3.: the main end point: intravenous thrombolytic therapy after 1D, compared with baseline, treatment group volume infarction patients increased significantly less than for the Pu enzyme treatment group (10.1 + 1.2 vs34.3 + 10.4ml, P=0.035). Secondary end point: thrombolytic therapy of 7D, compared with the baseline treatment group were significantly reduced infarct volume, and alteplase treatment groups were significantly different (-2.3 + 2.7 vs12.3 + 3.9ml, P=0.004), even small infarction at baseline the volume of.4. after thrombolytic therapy of hemorrhagic transformation: the primary end point: thrombolytic therapy 1D combined treatment group occurred in cases of bleeding into less than alteplase group, 8 (36%): 11 (44%). And the bleeding volume was significantly smaller than alteplase treatment group, combined treatment group occurred after hemorrhagic transformation (2.3 + 0.7 vs 4.5 + 1.2ml, P=0.012). The degree of hemorrhagic transformation, the combined treatment group was significantly higher than alteplase treatment group. The combined treatment group were hemorrhagic transformation in hemorrhagic infarction, no cerebral hemorrhage patients. While the alteplase treatment group in 36% patients out of the blood into the brain parenchyma hematoma. Shadow Rang further treatment of cerebral infarction. Malignant middle cerebral artery occurred in 1 patients within 24 hours before and after thrombolytic treatment of.5. occlusion syndrome score of neurological changes: the primary end point: thrombolytic therapy 1D, combination therapy in patients with clinical function better than alteplase treatment group, NIHSS score was 4 (0-8) vs 2 (2-8 the secondary end point), P=0.021.: 7d thrombolysis treatment, combined treatment group of patients with clinical function improved significantly better than the alteplase treatment group, NIHSS score was 2.5 (0-7) vs 1 (4-5), P=0.008. secondary end point: a follow-up of 90 days, the combined treatment group of neural function defect is less than that of alteplase treatment group. Combined treatment group M RS 0-1 percentage score (73%) was significantly higher than that of alteplase treatment group (32%), P=0.008. and 4-5 percentage is significantly less than the control group, and the 2-3 group with roughly the same proportion of two.6. complications and adverse events: two patients were died of myocardial infarction. The death and recurrence of cerebral infarction. The alteplase group in 3 patients with gastrointestinal bleeding, and the combined treatment group only 1 cases of gastrointestinal bleeding. More than 38 have occurred in the two group of 5 patients? C fever. Adverse reactions: two groups of patients with adverse events in the number of cases are o alteplase Group 8 (33), 6 in the combined therapy group (30). There was no discontinued due to adverse events and serious adverse events. The combined treatment group suspected pulmonary infection rate was 14% and the urinary tract infection rate was 9%; two kinds of infection alteplase treatment group were 12% and 8%. Comparison between groups P value was 1, the difference was not statistically significant. The two groups did not occur in other common or special treatment group adverse events in.7. patients complained of chest discomfort, no arrhythmia or atrioventricular block. Before and after treatment, blood pressure, heart rate and routine laboratory tests no significant fluctuations. The research conclusion fingolimod Lian Combined alteplase for intravenous thrombolysis of acute ischemic stroke 24 hours primary end point, including the infarction volume change, hemorrhagic transformation and improving clinical outcomes, combined treatment is better than that of alteplase. Good clinical effect of alteplase and fingolimod therapy may protect the blood-brain barrier and inflammatory reaction to reduce and fingolimod treatment was well tolerated, with no obvious adverse reaction. The limitation of this study is that the small sample is small, the best method of randomization is not used, the lack of a control group. The safety of acute ischemic stroke fingolimod, immune regulation and evaluation of other the protective effect to larger clinical trials of the central nervous system.

【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R743.3

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