三七总皂苷对急性缺血性卒中患者重组组织型纤溶酶原激活物静脉溶栓疗效及出血性转化的影响

目的探讨三七总皂苷对急性缺血性卒中患者重组组织型纤溶酶原激活物(rt-PA)静脉溶栓疗效和出血性转化的影响。方法共200例急性(发病至入院时间4.50 h)缺血性卒中患者采用随机数字表法随机分为常规rt-PA静脉溶栓组(对照组,100例)和rt-PA静脉溶栓联合三七总皂苷治疗组(治疗组,100例),分别于治疗前、静脉溶栓后24 h和14 d检测缺血-再灌注损伤指标[丙二醛(MDA)、超氧化物歧化酶(SOD)]、出血性转化指标[基质金属蛋白酶-9(MMP-9)、纤维连接蛋白(FN)]和神经功能指标[美国国立卫生研究院卒中量表(NIHSS)、Barthel指数(BI)],观察静脉溶栓后14 d药物不良反应和出血性转化发生率,评价静脉溶栓后12个月预后(病死率和BI评分)。结果治疗组患者血清SOD(P=0.000)和BI评分(P=0.000)高于,血清MDA(P=0.001)和MMP-9(P=0.001)、血浆FN(P=0.000)和NIHSS评分(P=0.006)低于对照组。rt-PA静脉溶栓联合三七总皂苷治疗后24 h,血清MDA(P=0.000)和MMP-9(P=0.000)、BI评分(P=0.000)升高,NIHSS评分降低(P=0.000);治疗后14 d,血清MDA(P=0.000)和MMP-9(P=0.000)反而降低,血清SOD(P=0.000)和BI评分(P=0.000)持续升高,血浆FN(P=0.000)和NIHSS评分(P=0.000)持续降低。静脉溶栓后14 d,治疗组患者出血性转化发生率低于对照组[9例(9%)对19例(19%);χ2=4.153,P=0.042)],药物不良反应发生率组间差异无统计学意义[14例(14%)对11例(11%);χ2=0.411,P=0.521]。静脉溶栓后12个月,两组病死率差异无统计学意义[5例(5%)对1例(1%);χ2=1.546,P=0.241],而治疗组生存患者BI评分高于对照组(88.51±11.49对84.47±9.83;t=2.451,P=0.015)。结论三七总皂苷可以减轻急性缺血性卒中患者rt-PA静脉溶栓后缺血-再灌注损伤,降低出血性转化发生率,改善患者预后,且安全性良好。     

急性脑梗死患者血浆纤溶酶原激活物及其抑制剂-1水平的动态变化及其与梗死面积的关系

目的 探讨急性脑梗死患者血浆组织型纤溶酶原激活物(t-PA)及其抑制剂-1(PAI-1)水平的动态变化及其与梗死面积的关系.方法 急性脑梗死患者100例,其中大面积脑梗死22例、小面积脑梗死36例、腔隙性脑梗死42例,采用发色底物显色法检测脑梗死患者病后24 h、2 d、14 d、21 d的血浆t-PA、PAI-1水平,与正常对照组比较;并比较不同面积脑梗死患者血桨t-PA、PAI-1水平.结果 与正常对照组比较,急性脑梗死患者病后24 h、2 d、14 d血浆t-PA水平显著降低,血浆PAI-1水平明显升高(均P＜0.01);病后21 d两者与正常对照组差异无统计学意义(均P＞0.05);大面积脑梗死患者t-PA水平明显低于小面积和腔隙性脑梗死患者,小面积脑梗死患者又明显低于腔隙性脑梗死患者(均P＜0.01);不同面积脑梗死组之间PAI-1水平未见明显差异(均P＞0.05).结论 脑梗死患者急性期血浆t-PA水平降低及PAI水平升高;脑梗死面积越大的患者血浆t-PA水平降低程度越明显,而血浆PAI-1水平与梗死面积无关.     

辛伐他汀对急性脑梗死患者血浆t-PA和PAI-1水平的影响

目的 探讨辛伐他汀对急性脑梗死(acute cerebral infarction,ACI)患者血浆t-PA和PAI-1水平的影响.方法 将50例急性脑梗死患者随机分为治疗组和对照组,2组均给予脱水、营养脑细胞等常规治疗,治疗组在常规治疗的基础上加用辛伐他汀,2组均未给予抗凝、溶栓、降纤治疗,测定用药前及用药4 周后的血浆 t-PA和PAI-1的含量.结果 2组用药前血浆t-PA和PAI-1的含量无明显差异(P＞0.05),治疗4周后治疗组血浆t-PA含量明显高于对照组(P＜0.05),PAI-1含量明显低于对照组(P＜0.05).结论 辛伐他汀能升高急性脑梗死患者血浆tPA-1含量,降低血浆PAI-1含量,提高体内纤溶状态,治疗急性脑梗死有效.     

HAT、SEDAN评分及相关脑血管病危险因素预测急性缺血性卒中溶栓后出血性转化临床研究

目的探讨溶栓后出血评分(HAT)、症状性溶栓出血危险因素评分(SEDAN)和相关危险因素预测急性缺血性卒中患者重组组织型纤溶酶原激活物(rt-PA)静脉溶栓后出血性转化的临床应用价值。方法共143例发病4.50 h内行rt-PA静脉溶栓且临床资料完整的急性缺血性卒中患者,根据溶栓治疗后头部CT所示分为出血性转化组(18例)和非出血性转化组(125例),二分类Logistic回归分析筛选静脉溶栓后发生出血性转化的危险因素、受试者工作特征(ROC)曲线评价HAT和SEDAN评分预测出血性转化的敏感性和特异性。结果单因素Logistic回归分析显示,心房颤动、入院时收缩压和血糖水平、发病早期CT呈低密度征象、溶栓时间窗、美国国立卫生研究院卒中量表(NIHSS)评分、HAT和SEDAN评分均为静脉溶栓后出血性转化危险因素(P0.05);代入二分类Logistic回归方程后,除发病早期CT呈低密度征象,其余各项均为静脉溶栓后发生出血性转化之危险因素。ROC曲线显示,HAT评分预测出血性转化灵敏度为94.40%、特异度为41.60%、曲线下面积0.70,SEDAN评分则为94.40%、65.62%和0.77。结论心房颤动、入院时收缩压和血糖水平、溶栓时间窗、NIHSS评分、HAT和SEDAN评分均为缺血性卒中静脉溶栓后发生出血性转化的危险因素,但以SEDAN评分预测价值较高。     

MMP-9在扩大时间窗急性脑梗死静脉溶栓出血转化中的意义

目的探讨基质金属蛋白酶-9(MMP-9)与扩大时间窗至发病6 h内急性脑梗死重组组织型纤溶酶原激活剂(rt-PA)静脉溶栓治疗的关系。方法对70例本院神经内科扩大时间窗内行rt-PA静脉溶栓的急性脑梗死患者分别测定溶栓前后的血浆MMP-9水平,并与急性脑梗死非溶栓对照组比较。结果急性脑梗死患者溶栓组、非溶栓对照组入院12 h后血浆MMP-9水平和入院时比较都有显著差异(P<0.05);有出血转化者MMP-9水平皆较无出血转化为高(P0.05)。结论急性脑梗死MMP-9表达水平与出血转化...     

25例急性脑梗死患者静脉溶栓治疗

目的 观察重组组织型纤溶酶原激活剂(rt-PA)早期静脉溶栓治疗急性脑梗死的疗效及安全性.方法 25例发病时间＜3 h的急性脑梗死患者接受rt-PA静脉溶栓治疗,剂量(0.6～0.9)mg/kg.溶栓前及溶栓后2 h、24 h及7 d接受美国国立卫生院卒中量表(NIHSS)评分,3个月接受改良Rankin评分,并观察安全性.结果 溶栓后7 d的NIHSS评分较基线值显著改善(P=0.04),20例完成3个月MRS评估者中,0～1分6例(30%),死亡2例(10%).症状性脑出血患者2例.基线NIHSS评分高(P=0.002)及完全前循环梗死型(P=0.01)者易发生症状性脑出血.结论 早期静脉溶栓治疗急性脑梗死能改善患者的远期预后.     

胶质纤维酸性蛋白与非溶栓性出血性转化关系的研究

目的探讨脑梗死患者血浆胶质纤维酸性蛋白水平变化对非溶栓性出血性转化的预测作用。方法选择78例人院时间<72h且头部MRI检查无出血的急性脑梗死患者,发病7～10d后复查MRI,梯度回波序列显示低信号为出血性转化;酶联免疫吸附法定量检测血浆胶质纤维酸性蛋白水平;并探讨影响出血性转化的可能危险因素。结果 78例患者中11例梯度回波序列呈现低信号。脑梗死组患者血浆胶质纤维酸性蛋白水平[(2798.46±1072.66)ng/L]与正常对照组[(2173.37±867.77)ng/L]之间,差异有统计学意义(P=0.000);其中出血性转化组血浆胶质纤维酸性蛋白水平[(3660.03±629.64)ng/L]明显高于非转化组[(2657.01±1066.89)ng/L]和正常对照组[(2173.37±867.77)ng/L;(P=0.000,P=0.005)]。多因素Logistic逐步回归分析显示,血浆胶质纤维酸性蛋白水平及房颤为出血性转化的危险因素(P=0.005,P=0.017)。结论急性脑梗死患者发病72h内血浆胶质纤维酸性蛋白水平高于2856.90 ng/L,对非溶栓性出血性转化的发生具有预测意义,可作为预测非溶栓性出血性转化的标志物之一。     

急性缺血性卒中重组组织型纤溶酶原激活剂静脉溶栓致出血性转化及其预后的危险因素分析

目的 探讨急性缺血性卒中重组组织型纤溶酶原激活剂(rt-PA)静脉溶栓后发生出血性转化(HT)的可能危险因素以及这些危险因素对患者预后的影响.方法 128例急性缺血性卒中患者发病6h内接受rt-PA静脉溶栓治疗,选取溶栓前临床和实验室资料,通过比较HT组与非HT组之间的差异,筛选与HT相关的可能危险因素,并进一步通过Logistic回归分析影响HT及其预后的独立危险因素.结果 128例溶栓患者有29例继发HT(22.66％),其中16例为症状性脑出血(12.50％),死亡2例,占HT的6.90％.Logistic回归分析表明房颤(OR=1.293,95％ CIl.224 ～1.589,P=0.00l)、早期CT改变(OR=2.452,95％ CI 1.132～3.309,P=0.034)、基线舒张压≥100 mm Hg(1 mm Hg=0.133 kPa,OR=9.265,95％ CI 1.435 ～ 59.836,P=0.019)、基线血糖≥11.1 mmol/L(OR=3.037,95％ CI0.252 ～ 57.593,P=0.047)、NIHSS评分＞15分(OR=8.752,95％CI 1.035 ～30.285,P=0.023)和溶栓时间窗＞3h(OR=98.74,95％CI 5.067 ～ 186.120,P=0.002)6项为HT独立危险因素,其中基线血糖≥11.1 mmol/L(OR=3.265,95％ CI 0.435 ～ 59.863,P=0.045)、NIHSS评分＞15分(OR=10.453,95％ CI 5.647～38.185,P=0.003)和溶栓时间窗＞3h(OR =2.541,95％CI 1.098 ～51.086,P=0.017)影响了HT患者的预后.结论 溶栓前的舒张压、血糖水平、神经功能缺损程度、CT低密度改变或水肿占位效应、房颤和溶栓时间窗是HT的独立危险因素,其中基线血糖水平、神经功能缺损程度和溶栓时间窗影响了溶栓后HT患者的预后.     

自发性蛛网膜下腔出血后血液及脑脊液纤溶活性的研究

目的探讨自发性蛛网膜下腔出血(SAH)后血及脑脊液(CSF)中纤溶活性的变化规律及正常CSF中的纤溶状态。方法组织型纤溶酶原激活物的活性(tPA:A)及纤溶酶原抑制物的活性 (PAI:A)测定采用发色底物法,纤溶酶原抑制物-1(PAI-1)及D-二聚体(D-D)定量测定采用酶联免疫吸附试验(ELISA)双抗体夹心法,血及CSF标本在SAH后0-3 d(急性期),4-9 d(再出血高峰期),及 14-21 d(吸收期)留取三次;正常对照组留取一次。结果 SAH患者血液中,急性期tPA:A显著低于对照组,并随病程延长显著升高,至14-21 d达正常水平,与对照组差异无显著意义;急性期PAI:A 及D-D水平显著高于对照组,并随病程延长而显著降低,至14-21 d降至正常水平,与对照组差异无显著意义;各期PAI-1含量与对照组差异无显著意义。对照绀CSF中,测不到tPA:A及PAI:A及 PAI-1,D-D测得值很小,为(0．28±0．36)mg/L。 SAH患者CSF中,各期测不到tPA:A及PAI:A,但 PAI-1含量急性期显著升高并随病程延长而显著降低,D-D急性期显著升高并随病程延长而显著降低,至14-21 d 与对照组无显著性差异。结论 SAH后血中不存在纤深活性亢进。对照组CSF中不含有纤溶酶系。SAH患者CSF中纤溶活性急性期升高而后降低,于14-21 d恢复到正常水平。再出血高峰期血及CSF中反映纤溶活性的指标变化均显著低于急性期,提示再出血与血及CSF中纤溶活性无关。故SAH后不宜长期大剂量应用抗纤溶药物来预防再出血。     

重组组织型纤溶酶原激活剂治疗心源性脑栓塞的疗效观察

目的观察重组组织型纤溶酶原激活剂(rt-PA)治疗心源性脑栓塞的临床疗效。方法将我院收治的62例心源性脑栓塞患者分为溶栓组32例和对照组30例。对照组行常规治疗,溶栓组在常规治疗的基础上行rt-PA溶栓治疗。于2组入院时及发病24h时,采用NIHSS量表分别对患者进行神经功能缺损评分;同时,予以患者复查头颅CT,统计2组患者出血性转化(HT)及症状性出血转化(SICH)的发生率;并检测2组治疗前后血清MMP-9的表达水平。另外,于2组治疗后第30天,再次根据NIHSS评分评价患者的远期治疗效果。结果发病24h后,溶栓组NIHSS评分低于对照组(P0.05);且溶栓组NIHSS早期改善率(56.25%)高于对照组(40%),(P0.05)。溶栓组HT、SICH的发生率依次为15.63%、12.5%,对照组依次为13.33%、10%,2组比较差异无统计学意义(P0.05);治疗前后2组患者平均血清MMP-9表达水平比较,差异均无统计学意义(P0.05)。治疗30d后,溶栓组总有效率为75%,对照组为56.67%,2组比较差异具有统计学意义(P0.05)。结论心源性脑栓塞患者溶栓时间窗内予以rt-PA溶栓治疗可有效提高近远期疗效,改善患者预后,且不会增加症状性出血转化的发生率,安全有效,值得临床推广应用。     

Tissue plasminogen activator, plasminogen activator inhibitor-1, and tissue plasminogen activator/plasminogen activator inhibitor-1 complex as risk factors for the development of a first stroke

BACKGROUND NAD PURPOSE: Abnormalities in the fibrinolytic system have been associated with an increased risk for stroke in a few studies. This study was designed to test whether plasma levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and tPA/PAI-1 complex could predict a first-ever stroke. METHODS: The study was an incident case-control study nested within the V?sterbotten Intervention Program and the Northern Sweden Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) cohorts. In this study 108 first-ever stroke cases were defined according to the MONICA classification, and 216 controls from the same cohort were randomly selected and matched for age, sex, sampling time, and geographic region. RESULTS: Stroke occurred on average 30 months after the blood sampling date. The mean plasma concentration of tPA/PAI-1 complex was higher for the stroke cases than for the controls (3.9 versus 3.0 microgram/L). In univariate regression analysis, significantly higher odds ratios were found for the tPA/PAI-1 complex as continuous variable. When divided into quartiles, the odds ratio was 2.74 for the highest quartile compared with the lowest. In the multivariate model, the tPA/PAI-1 complex remained an independent predictor for stroke. Additionally, tPA mass concentration quartiles 3 and 4 showed a significant association with all stroke as outcome. No association was found, however, for PAI-1. In subgroup analysis of cerebral hemorrhage (n=18), the mean tPA/PAI-1 complex level was higher for the cases than for the controls (4.8 versus 3.0 microgram/L), and in multivariate analysis including all controls (n=216), only tPA/PAI-1 complex remained significant. CONCLUSIONS: This prospective study shows that tPA/PAI-1 complex, a novel fibrinolytic marker, is independently associated with the development of a first-ever stroke, especially hemorrhagic stroke. This finding supports the hypothesis that disturbances in fibrinolysis precede a cerebrovascular event.     

Tissue plasminogen activator and plasminogen activator inhibitor in patients with acute ischemic stroke: relation to stroke etiology

Recent studies suggest that high plasma levels of tissue-type plasminogen activator (tPA) and its inhibitor (plasminogen activator inhibitor-1, PAI-1) are markers of an increased risk of atherothrombotic ischemic events such as stroke and myocardial infarction. In this prospective study, we measured tPA antigen, PAI-1 antigen and activity, as well as tPA/PAI-1 complex in patients with acute stroke. Stroke subtypes were classified according to the TOAST criteria. From 132 consecutively screened patients, 89 (100%) were enrolled in this study, including 42 patients (47%) with large artery atherosclerosis (LAA), 32 (36%) with small vessel occlusion (SVO), and 15 (17%) with cardioembolism (CE). Nineteen age-matched neurologic patients without manifestations of cerebrovascular disease served as control subjects (CS). Patients with acute stroke had significantly higher plasma levels of tPA antigen (p < 0.001), PAI-1 antigen (p < 0.05) and PAI activity (p < 0.05) than patients in the control group. t-PA antigen, PAI activity and tPA/PAI-1 complex levels were similar regardless of stroke etiology. Only PAI-1 antigen was lower in patients with cardioembolic stroke than in stroke patients with LAA (p < 0.05). Plasma tPA antigen, PAI-1 antigen, and PAI activity are significantly increased in patients with acute ischemic stroke. Except for PAI-1 antigen, this increase appears not to be related to the underlying stroke etiology.     

Admission fibrinolytic profile predicts clot lysis resistance in stroke patients treated with tissue plasminogen activator

Endogenous fibrinolysis inhibitors may be involved in t-PA resistance, decreasing stroke thrombolysis benefits. We aim to determine the impact of pretreatment levels of plasminogen activator inhibitor (PAI-1), lipoprotein(a), thrombin-activatable fibrinolysis inhibitor (TAFI) and homocysteine on arterial recanalization and outcome. Forty-four consecutive patients with acute proximal middle cerebral artery occlusion were studied, including assessment of transcranial Doppler artery patency. The neurological status was determined by NIH Stroke Scale (NIHSS) and long-term outcome with modified Rankin Scale (mRS). Patients who recanalized after t-PA infusion had lower PAI-1 levels than those who remained occluded. Similarly, patients who achieved dramatic clinical recovery at 12 hours exhibited significantly lower PAI-1 levels as those independent (mRS< or =2) at third month. We observed a trend towards lower lipoprotein p(a) in patients who achieved recanalization at 1 hour, whereas no relation was found between TAFI or homo-cysteine levels and recanalization. After a regression model was applied the only independent predictor of thrombolysis resistance was baseline PAI-1>34 ng/ml, such that high PAI-1 levels interfere with tPA-induced recanalization in stroke, predicting a higher susceptibility towards clot-lysis resistance and poor out-come.     

The effect of insulin treatment on the balance between tissue plasminogen activator and plasminogen activator inhibitor-1 in type 2 diabetic patients.

Beside hypercoagulation and hyperactivated platelets disturbances of the fibrinolytic system towards hypofibrinolysis have been reported to be associated with both glycemic and lipidemic derangement in diabetic patients. In the present prospective follow-up study the effect of 16 weeks insulin treatment and glycemic regulation on plasma levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), the main regulators of fibrinolysis, was investigated in 19 type-2 diabetic patients with secondary failure to sulphonylureas. A similar glycemic regulation was obtained in a control group of 10 type 2 diabetic patients with sufficient metabolic response to strict dietary treatment and continuation of sulphonylurea treatment. Compared to 27 healthy subjects levels of tPA and PAI-1 were not significantly increased in type 2 diabetic patients before metabolic intervention. Although a hypofibrinolytic state due to an increase of PAI-1 levels was previously reported in obese hyperinsulinemic patients, no effect of insulin treatment on both tPA- and PAI-1 levels was observed in the present study including patients with only slightly increased body mass index (median 26.0 kg/m2). By correlation analysis PAI-1 levels were significantly related to serum cholesterol (R = 0.52) and glycemic control (glucose R = 0.41) in the whole group of diabetic patients at entry and in both subgroups after 16 weeks of treatment (insulin group: cholesterol R = 0.46, HbA1c R = 0.51; sulphonylurea group: cholesterol R = 0.59, HbA1c R = 0.58). In healthy subjects tPA and PAI-1 was correlated to serum insulin (R = 0.54, R = 0.56) and triglycerides (R = 0.46, R = 0.40).(ABSTRACT TRUNCATED AT 250 WORDS)     

水蛭提取液对培养的大鼠脑皮质微血管内皮细胞分泌组织型纤溶酶原激活物和纤溶酶原激活剂抑制物1的影响

目的探讨水蛭提取液(HEL)对培养的大鼠脑皮质微血管内皮细胞分泌组织型纤溶酶原激活物(tPA)、纤溶酶原激活剂抑制物1(PAI-1)的影响。方法建立大鼠大脑皮质微血管内皮细胞培养实验模型。MTT法筛选HEL的有效浓度。检测培养上清液的tPA、PAI-1含量与活性变化,RT-PCR检测经HEL治疗组与生理盐水对照组处理后的微血管内皮细胞tPA与PAI-1的表达,免疫组化检测两组微血管内皮细胞tPA的表达。结果 HEL在一定浓度范围内(0.25～1mg/μl)可促进微血管内皮细胞的生长,有剂量依赖关系(P<0.05)。HEL治疗组较生理盐水对照组能促进培养的大鼠脑皮质微血管内皮细胞分泌tPA,同时提高其活性,促进tPA mRNA的表达及tPA免疫活性表达,且呈剂量依赖性表达增强(P<0.01)。结论 HEL在体外能激活内源性纤溶系统。     

Relationships between euglobulin clot lysis time and the plasma levels of tissue plasminogen activator and plasminogen activator inhibitor 1

The relationships between tissue plasminogen activator (tPA), its fast acting inhibitor (PAI-1) and euglobulin clot lysis time (ELT) were investigated with healthy volunteers' plasma. Turbidimetric clot lysis assay by the microtiter plate reader was utilized for ELT with a slight modification. Both tPA and PAI-1 showed the significant correlation with ELT. tPA had a significantly positive, not negative, correlation with ELT (R = 0.387, p less than 0.001). Higher correlation coefficients (R = 0.580, p less than 0.001 and R = 0.599, p less than 0.001) were obtained between ELT and total PAI-1 or free PAI-1 than tPA or tPA-PAI-1 complex (R = 0.427, p less than 0.001). The positive correlation was also obtained between tPA and PAI-1. These data suggest that PAI-1 is a highly important factor for ELT, especially, the amounts of free PAI-1 being the key factor to determine the ELT, which can represent the potential activity of the fibrinolytic system.     

Effect of peptides on the inactivation of tissue plasminogen activator by plasminogen activator inhibitor-1 and on the binding of tissue plasminogen activator to endothelial cells

The effectiveness of tissue plasminogen activator (tPA) in thrombolytic therapy is dependent upon the rate at which therapeutically administered tPA reaches the clot site and the proportion of that tPA which is enzymatically active. Interactions between tPA and its main plasma inhibitor (PAI-1) and between tPA and the endothelial cells lining blood vessels are two factors which may limit efficacy. In an attempt to identify the regions of the tPA molecule involved in these interactions, we have examined a series of synthetic peptides with amino acid sequences corresponding to different regions of the tPA molecule for their ability to protect tPA from inactivation by PAI-1 and for their ability to reduce the binding of tPA to endothelial cells. Three peptides were identified which were especially effective at maintaining tPA activity in the presence of PAI-1 and three others were found which had a lesser effect. These same peptides were also found to inhibit the binding of tPA to endothelial cells. This suggests that the same regions of the tPA molecule are involved in both processes. None of the peptides inhibited the binding of tPA to fibrin. These peptides may serve as models for the development of agents for enhancing the activity of both endogenous tPA and of tPA administered in thrombolytic therapy.     

Antiactin-targeted immunoliposomes ameliorate tissue plasminogen activator-induced hemorrhage after focal embolic stroke.

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by serious risks of intracerebral hemorrhage. In this study, the authors show that a novel antiactin-targeted immunoliposome significantly reduced tPA-induced hemorrhage in an established rat model of embolic focal stroke. Spontaneously hypertensive rats were subjected to focal ischemia using homologous blood clot emboli. Delayed administration of tPA (10 mg/kg, 6 hours after ischemia) induced intracerebral hemorrhage at 24 hours. In control rats treated with tPA plus vehicle, hemorrhage volumes were 9.0 +/- 2.4 uL (n = 7). In rats treated with tPA plus antiactin immunoliposomes, hemorrhage volumes were significantly reduced to 4.8 +/- 2.7 uL (n = 8, P < 0.05). No significant effects were seen when rats were treated with tPA plus a nontargeted liposome (7.8 +/- 2.1 uL, n = 9). Fluorescent immunohistochemistry showed that rhodamine-labeled targeted liposomes colocalized with vascular structures in ischemic brain that stained positive for endothelial barrier antigen, a marker of cerebral endothelial cells. These data suggest that immunoliposomes may ameliorate vascular membrane damage and reduce hemorrhagic transformation after thrombolytic therapy in cerebral ischemia.     

Cigarette smoking impairs bradykinin-stimulated tissue plasminogen activator release in human coronary circulation

BACKGROUND: Cigarette smoking is a major risk factor for acute coronary thrombosis. Bradykinin (BK) can induce the release of tissue plasminogen activator (tPA) from the coronary vasculature. The purpose of this study was to investigate whether smoking reduces BK-stimulated tPA release in human coronary circulation. MATERIALS AND METHODS: We examined two groups: 20 current smokers and 19 nonsmokers. By cardiac catheterization, graded doses of BK (0.2, 0.6 and 2.0 microg/min) and papaverine (PA) (12 mg) were administered into the coronary artery. Coronary blood flow (CBF) was measured using a Doppler flow wire. Blood samples from the aorta (Ao) and coronary sinus (CS) were assayed. RESULTS: BK increased both coronary artery diameter (CD) and CBF to a similar extent in the two groups. The net coronary tPA release was dose-dependently increased by BK in the two groups, but the degree of this increase in current smokers was significantly lower than that in nonsmokers. BK did not change plasminogen activator inhibitor type 1 (PAI 1) levels in either group. PA did not alter either tPA or PAI-1 levels in either group. CONCLUSIONS: These results suggest that cigarette smoking deteriorates coronary fibrolytic activity, independent of changes in CBF. These findings can at least partly explain the higher risk of coronary thrombosis in smokers.     

Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies

Today there exists only one FDA-approved treatment for ischemic stroke; i.e., the serine protease tissue-type plasminogen activator (tPA). In the aftermath of the failed stroke clinical trials with the nitrone spin trap/radical scavenger, NXY-059, a number of articles raised the question: are we doing the right thing? Is the animal research truly translational in identifying new agents for stroke treatment? This review summarizes the current state of affairs with plasminogen activators in thrombolytic therapy. In addition to therapeutic value, potential side effects of tPA also exist that aggravate stroke injury and offset the benefits provided by reperfusion of the occluded artery. Thus, combinational options (ultrasound alone or with microspheres/nanobubbles, mechanical dissociation of clot, activated protein C (APC), plasminogen activator inhibitor-1 (PAI-1), neuroserpin and CDP-choline) that could offset tPA toxic side effects and improve efficacy are also discussed here. Desmoteplase, a plasminogen activator derived from the saliva of Desmodus rotundus vampire bat, antagonizes vascular tPA-induced neurotoxicity by competitively binding to low-density lipoprotein related-receptors (LPR) at the blood-brain barrier (BBB) interface, minimizing the tPA uptake into brain parenchyma. tPA can also activate matrix metalloproteinases (MMPs), a family of endopeptidases comprised of 24 mammalian enzymes that primarily catalyze the turnover and degradation of the extracellular matrix (ECM). MMPs have been implicated in BBB breakdown and neuronal injury in the early times after stroke, but also contribute to vascular remodeling, angiogenesis, neurogenesis and axonal regeneration during the later repair phase after stroke. tPA, directly or by activation of MMP-9, could have beneficial effects on recovery after stroke by promoting neurovascular repair through vascular endothelial growth factor (VEGF). However, any treatment regimen directed at MMPs must consider their pleiotropic nature and the likelihood of either beneficial or detrimental effects that might depend on the timing of the treatment in relation to the stage of brain injury.