| Objective and Backgroud:Acute ischemic stroke(AIS) is the most common type of stroke, with high morbidity, high mortality and high morbidity characteristics,serious harm to the patient’s health and life. effective treatment or not after AIS will directly affect the prognosis. At present, for patients of onset of 3-4.5 hours,recombinant tissue plasminogen activator- alteplase(rt PA),the only evidence-based medicine has been proven effective in the treatment of acute stroke as thrombolytic agents has been widely used all over the world. However brain artery recanalization, inevitably there will be reperfusion injury associated with rt PA, including hemorrhagic transformation or mass effect of brain edema. The mechanism of hemorrhagic transformation may be reperfusion injury, collateral circulation establishment and so on. Reperfusion injuries often weaken or offset benefits of thrombolytic therapy, and even leads to the patient’s symptoms worsen. How to solve the reperfusion injury problems become the key of rt PA treatment. Immune and inflammatory responses are the key role in the AIS pathphysiology. Immune inflammatory signals involved in all stages of the ischemic cascade. Ischemic stroke within 4.5 hours that applications rt PA thrombolytic therapy, inflammation promote hemorrhagic transformation and vasogenic edema and reperfusion injury.As sphingosine analogue, Fingolimod can effect on sphingosine-1-phosphate(S1P) receptor on the lymphocyte surface by phosphorylation, inhibits the egress of lymphocytes from lymph nodes and limits their recirculation, thus preventing the infiltration of immune cells of the central nervous system(CNS). Therefore, we will assume that inhibit the inflammatory response may be beneficial in acute stroke thrombolysis reperfusion injury treatment. Early animal models and clinical validation study demonstrate that as novel immunomodulatory agents fingolimod can significantly reduce cerebral lesions expand and edema around the hematoma after intracerebral hemorrhage, and has a protective effect for BBB permeability, effectively improve the patient prognosis; however, for AIS patients who treatment with intravenous alteplase thrombolysis(the first onset of <4.5 hours), safety and fficacy of fingolimod is unknown. The purpose of this study is short-term and long-term clinical outcomes,the impact of the primary end points and secondary end pointsand the safety for patients with AIS who intravenous thrombolytic therapy combined with fingolimod.Method:The patients of AIS who onset within 4.5 h were evaluated seriously by intravenous thrombolysis and fingolimod Indications, 25 cases as a control group who received alteplase treatment, 22 cases as a treament group who received alteplase combined with fingolimod treatment. Before and after intravenous rt PA thrombolytic therapy, treament group of patients administered fingolimod(0.5mg/day × 3 days). Before and after treatment, we detect the circulating blood lymphocyte subsets changes(CD4+T, CD8+T, CD19+B and the CD56+Natural Killer cells) for all patients by flow cytometry, evaluated neurological function of NIHSS and m RS,evaluated MRI images to calculate infarct volume change, the rate of hemorrhagic transformation and bleeding volume, and observed whether there is any adverse events, whether there are significant statistical differences within treament group and the control group. We want to demonstrate whether alteplase combined with fingolimod treatment can reduce the hemorrhage and infarction volume, and improved clinical results.Results:1. administration of fingolimod 0.5mg for 1 day, circulating blood CD4 + T, CD8 + T, CD19 + B and the CD56 + natural killer cells of treament group were reduced stability, and this downward trend may continue for 7th day. And 90 th days, these circulating blood lymphocyte subsets were restored to baseline levels. Hoverer the control group of patients had no lymphopenia.2. In treatment group 14 patients(64%) obtained vascular recanalization varying degrees, in the control group 17 patients(68%) obtained recanalization. Recanalization rate had no statistical difference(P = 0.77) between the two groups.3. infarct volume changes: the primary endpoint,1d after thrombolytic therapy, the infarct volume increase of treatment group compared with baseline were significantly less than control group(10.1±1.2 vs 34.3±10.4ml, P=0.035). Secondary endpoints,7d after thrombolytic therapy, the infarct volume of reatment group was significantly reduced compared with baseline, there are significant differences compared with control group(-2.3±2.7 vs 12.3±3.9ml, P=0.004), even less than the baseline infarct volume.4. hemorrhagic transformation after thrombolytic therapy: the primary endpoint: 1d after thrombolytic therapy, the number of hemorrhagic transformation in the treatment group had fewer than control group, 8(36%): 11(44%). And bleeding volume in the treatment group was significantly less than control group(2.3 ± 0.7 vs 4.5 ± 1.2ml, P = 0.012). In terms of the degree of hemorrhagic transformation, the treatment group was significantly less than the control group. Hemorrhagic transformation of treatment group was hemorrhagic infarction, and no parenchymal hematoma. In the control group, 36% of patients were parenchymal hematoma, affected the further treatment of cerebral infarction.5. The changes for neurological function: The primary endpoint, thrombolytic therapy for 1d, improving clinical function of treatment group was better than control group, NIHSS score of 4(0-8) vs 2(2-8), P=0.021. Secondary endpoints, thrombolytic therapy for 7d, improving clinical function of treatment group was significantly better than control group, NIHSS score of 2.5(0-7) vs 1(4-5), P=0.008. Secondary endpoints, follow-up of 90 days, the neurological deficit of treatment group had less than control group. For m RS, in treatment group the proportion of score 0-1(73%) was significantly higher than control group(32%), P=0.008. And score 4-5 was significantly less than the control group.6. Complications and adverse events: There were no deaths occurred in patients, no patients with myocardial infarction and recurrence of cerebral infarction. In the control group, 3 cases had gastrointestinal bleeding, while the treatment group only had 1 case of gastrointestinal bleeding. In both groups, five patients occurred fever which higher than 38 C.Adverse reactions: suspected lung infection and urinary tract infection occurred in 14% and 9% of the treatment group and in 12% and 8% of the control group, respectively.7. No recipient of fingolimod complained of chest discomfort. ECG monitoring found no cardiac arrhythmia or atrioventricular blocks. In addition, blood pressure, heart rate and routine laboratory investigations before and after the treatment showed no obvious fluctuationsConclusion:In this study, the primary end point including infarction volume change, hemorrhagic transformation and improvements in clinical outcomes, fingolimod combined with alteplase therapy is superior than the pure alteplase treatment.Those good clinical effects of combined treatment might related to reduction of inflammation and protection for the blood brain barrier. Combination therapy of fingolimod and alteplase was well tolerated, no significant adverse reactions. The limitations of this study lies in the small sample, did not choose the better way to randomized, the lack of the parallel control group. The security, immune regulation and other protective effect on the central nervous system that application fingolimod in acute phase of Ischemic stroke need to be assessment through more large-scale clinical trials. |
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