本文選題：急性缺血性腦卒中 + 芬戈莫德�。� 參考：《天津醫(yī)科大學(xué)》2016年博士論文

【摘要】：研究目的與內(nèi)容:急性缺血性腦卒中(acute ischemic stroke,AIS)是最常見(jiàn)的腦卒中類型,具有高發(fā)病率、高致死率和高致殘率的特點(diǎn),嚴(yán)重危害患者的健康和生命。AIS后能否進(jìn)行有效的治療將直接影響患者的預(yù)后。目前對(duì)于發(fā)病3-4.5小時(shí)內(nèi)的患者,重組組織型纖溶酶原激活劑-阿替普酶(Recombinant Tissue Plasminogen Activato-Alteplase,rt PA)作為目前唯一被循證醫(yī)學(xué)證明有效治療急性腦卒中的溶栓藥物,在國(guó)內(nèi)外已經(jīng)得到廣泛應(yīng)用。然而阻塞的腦動(dòng)脈再通后,不可避免會(huì)出現(xiàn)與rt PA相關(guān)的腦再灌注損傷,包括出血轉(zhuǎn)化或占位性腦水腫等。出血性轉(zhuǎn)化的發(fā)生機(jī)制可能與血管再通、再灌注損傷、側(cè)支循環(huán)建立等有關(guān)。再灌注損傷往往減弱或抵消溶栓治療所帶來(lái)的益處,甚至?xí)䦟?dǎo)致患者癥狀的加重。如何解決再灌注損傷問(wèn)題成為rt PA治療的關(guān)鍵。免疫炎癥反應(yīng)在AIS病理生理學(xué)中占具關(guān)鍵地位。免疫炎癥信號(hào)參與了缺血后級(jí)聯(lián)反應(yīng)的的所有階段。缺血性腦卒中4.5小時(shí)內(nèi)應(yīng)用rt PA溶栓治療后,炎癥是促進(jìn)出血轉(zhuǎn)化和血管源性水腫等再灌注損傷重要因素。芬戈莫德(Fingolimod,FTY720)作為鞘氨醇類似物作用于鞘氨醇-1-磷酸受體,在體內(nèi)經(jīng)磷酸化后與淋巴細(xì)胞表面的S1P受體結(jié)合,改變淋巴細(xì)胞的遷移,促使淋巴細(xì)胞進(jìn)入淋巴組織,阻止其離開(kāi)淋巴組織進(jìn)入周圍循環(huán),進(jìn)而防止這些免疫細(xì)胞浸潤(rùn)中樞神經(jīng)系統(tǒng)(CNS),從而達(dá)到免疫抑制的效果。因此,我們假設(shè)抑制炎癥反應(yīng)可能將會(huì)是有利于急性腦卒中溶栓后再灌注損傷的治療。前期的動(dòng)物模型試驗(yàn)及臨床驗(yàn)證性試驗(yàn)證明芬戈莫德作為新型免疫調(diào)節(jié)劑,可以明顯減少腦梗死灶的擴(kuò)大以及腦出血后血腫周圍水腫,并對(duì)BBB通透性有保護(hù)作用,有效改善了患者的預(yù)后;然而,對(duì)于靜脈阿替普酶溶栓治療的AIS患者(首次發(fā)病4.5小時(shí)),芬戈莫德早期治療的安全性和有效性尚不可知。本研究目的在于,阿替普酶靜脈溶栓聯(lián)合芬戈莫德治療對(duì)AIS患者的近遠(yuǎn)期臨床結(jié)果、主要終點(diǎn)和次要終點(diǎn)等方面的影響,并探討其安全性。研究方法:我們對(duì)發(fā)病4.5h內(nèi)AIS患者進(jìn)行嚴(yán)格靜脈溶栓及口服芬戈莫德適應(yīng)征評(píng)估后,共篩選了47例患者進(jìn)入本研究,其中阿替普酶治療組25例作為對(duì)照組,阿替普酶聯(lián)合芬戈莫德治療組22例為實(shí)驗(yàn)組。實(shí)驗(yàn)組患者在靜脈rt PA溶栓治療前后,服用芬戈莫德(0.5mg/次,1次/天×3天)。治療前后所有入組患者應(yīng)用流式細(xì)胞學(xué)技術(shù)檢測(cè)循環(huán)血淋巴細(xì)胞亞群變化(CD4+T,CD8+T,CD19+B和CD56+自然殺傷細(xì)胞),對(duì)患者神經(jīng)功能進(jìn)行NIHSS和m RS評(píng)分,通過(guò)治療前后頭MRI影像計(jì)算梗死體積變化、出血轉(zhuǎn)化率及出血體積,以及觀察是否存在不良事件情況,通過(guò)試驗(yàn)組與對(duì)照組比較是否存在統(tǒng)計(jì)學(xué)差異。論證通過(guò)阿替普酶聯(lián)合芬戈莫德治療,是否可以減少AIS患者出血轉(zhuǎn)化及梗死體積,改善臨床結(jié)果。研究結(jié)果:1.口服給予芬戈莫德0.5mg后24小時(shí),聯(lián)合治療組患者循環(huán)血中CD4+T,CD8+T,CD19+B和CD56+自然殺傷細(xì)胞均有不同程度的穩(wěn)定減少,并且這種下降趨勢(shì)可以持續(xù)到第7天時(shí)。而90天時(shí),循環(huán)血中這些淋巴細(xì)胞亞群均恢復(fù)到基線期水平。而對(duì)照組患者無(wú)淋巴細(xì)胞減少。2.阿替普酶靜脈溶栓后,聯(lián)合治療組中14例(64%)患者存在不同程度的血管再通,對(duì)照組17例(68%)的患者閉塞的血管再通。血管再通率在兩組之間沒(méi)有差別(P=0.77)。3.溶栓治療前后梗死體積變化:主要終點(diǎn):靜脈溶栓治療1d后,與基線期比較,聯(lián)合治療組患者梗死體積增加量明顯小于阿替普酶治療組(10.1±1.2 vs34.3±10.4ml,P=0.035)。次要終點(diǎn):溶栓治療7d時(shí),與基線期比較聯(lián)合治療組患者梗死體積明顯減小,與阿替普酶治療組比較有明顯差異(-2.3±2.7 vs12.3±3.9ml,P=0.004),甚至小于基線期梗死體積。4.溶栓治療后出血轉(zhuǎn)化:主要終點(diǎn):溶栓治療1d時(shí)聯(lián)合治療組發(fā)生出血轉(zhuǎn)化的例數(shù)少于阿替普酶組,8(36%):11(44%)。并且聯(lián)合治療組發(fā)生出血轉(zhuǎn)化后出血體積明顯小于阿替普酶治療組(2.3±0.7 vs 4.5±1.2ml,P=0.012)。在出血轉(zhuǎn)化程度方面,聯(lián)合治療組明顯較阿替普酶治療組輕。聯(lián)合治療組中出血轉(zhuǎn)化均為出血性梗死,無(wú)腦實(shí)質(zhì)出血患者。而阿替普酶治療組中有36%患者的出血轉(zhuǎn)化為腦實(shí)質(zhì)血腫,影響了進(jìn)一步腦梗死治療。其中1例患者24小時(shí)內(nèi)發(fā)生惡性大腦中動(dòng)脈閉塞綜合征。5.溶栓治療前后神經(jīng)功能評(píng)分變化:主要終點(diǎn):溶栓治療1d,聯(lián)合治療組患者臨床功能改善好于阿替普酶治療組,NIHSS分值為4(0-8)vs 2(2-8),P=0.021。次要終點(diǎn):溶栓治療7d,聯(lián)合治療組患者臨床功能改善明顯好于阿替普酶治療組,NIHSS分值為2.5(0-7)vs 1(4-5),P=0.008。次要終點(diǎn):隨訪90天時(shí),聯(lián)合治療組神經(jīng)功能缺損少于較阿替普酶治療組,聯(lián)合治療組m RS分值中0-1分比例(73%)明顯高于阿替普酶治療組(32%),P=0.008。并且4-5分比例明顯少于對(duì)照組,而2-3分比例兩組大致相同。6.并發(fā)癥和不良事件:兩組患者中均未發(fā)生死亡、心肌梗死、腦梗死復(fù)發(fā)。阿替普酶組中有3例患者出現(xiàn)胃腸道出血,而聯(lián)合治療組中僅有1例發(fā)生了胃腸道出血。兩組中均有5例患者發(fā)生高于38?C的發(fā)熱。不良反應(yīng):兩組患者發(fā)生不良事件例數(shù)分別是,阿替普酶組8(33),聯(lián)合治療組6(30)。均未發(fā)生因不良事件停藥及嚴(yán)重不良事件。聯(lián)合治療組中疑似肺部感染率為14%和尿路感染率為9%;阿替普酶治療組中兩類感染分別為12%和8%,組間比較P值為1.00,無(wú)統(tǒng)計(jì)學(xué)差異。兩組患者中均未發(fā)生其他常見(jiàn)或特殊不良事件。7.聯(lián)合治療組中患者未主訴胸部不適,未發(fā)現(xiàn)心律失�；蚍渴覀鲗�(dǎo)阻滯。治療前后血壓、心率以及常規(guī)實(shí)驗(yàn)室檢查無(wú)明顯波動(dòng)。研究結(jié)論芬戈莫德聯(lián)合阿替普酶靜脈溶栓治療急性缺血性腦卒中24小時(shí)主要終點(diǎn)指標(biāo),包括梗死體積變化,出血轉(zhuǎn)化以及臨床結(jié)果改善方面,聯(lián)合治療優(yōu)于單純阿替普酶治療。阿替普酶與芬戈莫德聯(lián)合治療的良好臨床效應(yīng)可能與保護(hù)血腦屏障及減少炎癥反應(yīng)有關(guān)。并且芬戈莫德治療患者耐受性良好,無(wú)明顯不良反應(yīng)。本項(xiàng)研究的局限性在于小樣本小,未選用最佳的隨機(jī)化方法,缺乏平行對(duì)照組。缺血性腦卒中急性期應(yīng)用芬戈莫德的安全性、免疫調(diào)節(jié)作用以及對(duì)中樞神經(jīng)系統(tǒng)其他保護(hù)作用需要更大規(guī)模的臨床試驗(yàn)進(jìn)行研究評(píng)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.

【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R743.3

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