Effects of additional treatment of sarpogrelate to aspirin therapy on platelet aggregation and plasma plasminogen activator inhibitor activity in patients with stable effort angina

Introduction

Serotonin is secreted from platelets at sites of endothelial injury, where it promotes thrombogenic reactions. Serotonin is reported to be associated with not only coronary artery disease but also cardiac events.

Materials and Methods

We studied 33 patients with stable effort angina (SEA) (11 patients with multivessel disease (MVD) and 22 patients with singlevessel disease (SVD)) and 25 patients with chest pain syndrome (CPS). Sarpogrelate was administered to 22 of 33 patients with SEA in addition to aspirin therapy, and platelet aggregation, plasma serotonin concentration, and plasma plasminogen activator inhibitor (PAI) activity were measured before and 1 week after administration.

Results and Conclusions

Serotonin level was higher in patients with MVD than in those with SVD (p < 0.05) and in those with CPS (p < 0.001). The formation of small-sized platelet aggregates was significantly higher in the high serotonin group than in the low serotonin group of SEA patients. The formation of large-sized platelet aggregates was significantly decreased by administration of sarpogrelate (P < 0.05). The formation of small- or medium-sized aggregates was not significantly decreased. Plasma PAI activity decreased significantly (P < 0.05) although the plasma serotonin concentration did not show significant change by administration of sarpogrelate. Plasma serotonin level is increased in relation to severity of coronary artery disease and plasma serotonin level is associated with increased platelet aggregation. Administration of sarpogrelate in addition to aspirin therapy reduces the increased platelet aggregation and PAI activity, and it may indicate that additional administration of sarpogrelate is useful for patients with SEA.     

A combination of a thrombin inhibitor and dexamethasone prevents the development of experimental disseminated intravascular coagulation in rats

INTRODUCTION: Disseminated intravascular coagulation (DIC) is a serious and potentially lethal complication of severe sepsis. DIC is characterised primarily by widespread platelet aggregation and fibrin deposition, followed by consumption of platelets, coagulation factors, and inhibitors. The aim of the study was to evaluate the efficacy of the active-site thrombin inhibitor melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, in reducing fibrinogen and platelet consumption in blood and fibrin deposition in organs, in an experimental endotoxinaemia rat model. MATERIALS AND METHODS: In this model, DIC was induced by an intravenous injection of endotoxin (1 mg/kg). Melagatran was compared with unfractionated heparin and the synthetic glucocorticoid analogue dexamethasone. Animals were divided into 16 treatment groups in which high and low doses of each agent were tested alone and in combination with melagatran. RESULTS: Fibrinogen consumption was reduced by melagatran, dexamethasone, and heparin, and was completely prevented by melagatran in combination with dexamethasone. Platelet consumption was partially reduced by melagatran, unfractionated heparin, and dexamethasone, but complete protection was observed only with melagatran in combination with dexamethasone. Melagatran in combination with dexamethasone or heparin protected the liver and spleen from fibrin deposition. CONCLUSION: In this experimental DIC rat model, the direct thrombin inhibitor melagatran given together with dexamethasone protected against the consequences of activated haemostasis.     

Evaluation of a porcine model to study in vivo platelet activation

INTRODUCTION: In order to investigate if decompression sickness involves platelet activation an animal model was evaluated. MATERIALS AND METHODS: Twenty-four thiopentone-midazolam-fentanyl-anaesthetized pigs in four groups received 5-min infusions of adenosine diphosphate (25 mg/kg) or platelet activating factor (0.4 microg/kg). Groups 1 and 2 (adenosine diphosphate, n=6 and platelet activating factor, n=6) were studied for 30 min and then sacrificed. Groups 3 and 4 (adenosine diphosphate, n=6 and platelet activating factor, n=6) were sacrificed immediately afterwards to study short-term changes. Haemodynamics, platelet counts and post mortem lung platelet aggregates were registered. Groups 1 and 2 also had indium platelet labelling, lung scintigraphy and platelet accumulation index calculations performed. RESULTS: Adenosine diphosphate induced immediate and more profound transient shocks. Platelet and leukocyte count decreases and occurrences of post mortem lung platelet aggregates were significantly more profound in the 5-min adenosine diphosphate group (Group 3) than in the platelet activating factor group (Group 4). With platelet labelling there were positive platelet accumulation index trends in the 30-min adenosine diphosphate group (Group 1). Adenosine diphosphate also produced platelet aggregation in platelet-rich porcine plasma. Only adenosine diphosphate (an intermediate platelet agonist) showed signs of platelet activation when considering all platelet parameters. The model should be further evaluated with different bolus doses of adenosine diphosphate, but may be used to evaluate if gas bubbles introduced into the circulation (as with decompression sickness), or possibly if clinical drugs, might produce platelet activation in vivo.     

PAI-1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injury

Fibrotic disorders of the lung are associated with perturbations in the plasminogen activation system. Specifically, plasminogen activator inhibitor‐1 (PAI‐1) expression is increased relative to the plasminogen activators. A direct role for this imbalance in modulating the severity of lung scarring following injury has been substantiated in the bleomycin model of pulmonary fibrosis. However, it remains unclear whether derangements in the plasminogen activation system contribute more generally to the pathogenesis of lung fibrosis beyond bleomycin injury. To answer this question, we employed an alternative model of lung scarring, in which type II alveolar epithelial cells (AECs) are specifically injured by administering diphtheria toxin (DT) to mice genetically engineered to express the human DT receptor (DTR) off the surfactant protein C promoter. This targeted AEC injury results in the diffuse accumulation of interstitial collagen. In the present study, we found that this targeted type II cell insult also increases PAI‐1 expression in the alveolar compartment. We identified AECs and lung macrophages to be sources of PAI‐1 production. To determine whether this elevated PAI‐1 concentration was directly related to the severity of fibrosis, DTR⁺ mice were crossed into a PAI‐1‐deficient background (DTR⁺: PAI‐1^?/?). DT administration to DTR⁺: PAI‐1^?/? animals caused significantly less fibrosis than was measured in DTR⁺ mice with intact PAI‐1 production. PAI‐1 deficiency also abrogated the accumulation of CD11b⁺ exudate macrophages that were found to express PAI‐1 and type‐1 collagen. These observations substantiate the critical function of PAI‐1 in pulmonary fibrosis pathogenesis and provide new insight into a potential mechanism by which this pro‐fibrotic molecule influences collagen accumulation. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Expression and Significance of Plasminogen Activator Inhibitor in Osteoarthritis Synovial Membrane

目的探讨两种纤溶酶原激活物抑制因子(PAI)在骨关节炎的发生发展中的意义。方法采用免疫组化方法检测滑膜组织中尿激酶型纤溶酶原激活物(uPA),组织型纤溶酶原激活物(tPA),PAI-1,PAI-2的表达。结果骨关节炎滑膜中PAI-1,PAI-2的阳性表达比例高于正常滑膜(P<0.05),骨关节炎滑膜中PAI-1与uPA、tPA蛋白表达阳性细胞百分比呈直线正相关关系。结论 PAI可能与骨关节炎软骨退变表现为长期慢性过程有关。     

高血压病患者脑腔隙性病变危险因素分析

目的：分析高血压病患者合并腔隙性脑梗塞的危险因素。方法：观察７５例住院的高血压病患者,以头颅人振扫描有无腔隙性脑梗塞分成二组,并进行血脂、血黏度、血小权聚集率、血尿酸、尿微量白蛋白、纤溶、糖耐量试验及动态血压检查,并进行组间比较及Ｌｏｇｉｓｔｉｃ回归统计分析。结果：高血压病合并腔梗组高密度脂蛋白、微量白蛋白尿、ＰＡＩ－１、平均收缩压、最大收缩压、糖负荷后最大胰岛素及胰岛素释放曲线下面积与非腔梗组有     

通心络对急性脑梗死治疗作用基础与临床研究

目的通心络对急性脑梗死治疗作用的基础和临床研究。方法135例患者随机分成治疗组和对照组。治疗前后查Tin、t—PA、PAl、AⅢ、ACA、D—dinaer、tHey、Ps、Pc,并于15天、30天、90天行ESS和Barthel指数评分。结果与治疗前相比,治疗后两组患者血Till、PAl显著下降(P相似文献   

Lapachol suppresses cell proliferation and secretion of interleukin-6 and plasminogen activator inhibitor-1 of fibroblasts derived from hypertrophic scars

Objectives The pathogenesis and therapy of hypertrophic scar have not yet been established. Our aim was to investigate the antiproliferative and antisecretory effects of lapachol, isolated from the stem bark of Avicennia rumphiana Hall. f., on hypertrophic scar fibroblasts. Methods The effects of lapachol on hypertrophic scar fibroblast proliferation were measured using the MTT assay, cell‐cycle analyses and lactate dehydrogenase assays. The type I collagen α‐chain (COL1A1), interleukin‐6 (IL‐6) and plasminogen activator inhibitor‐1 (PAI‐1) mRNA and/or protein levels of hypertrophic scar‐fibroblasts were quantitated by real‐time PCR and ELISA. Key findings Lapachol at 25 and 50 µm significantly inhibited the in vitro proliferation of hypertrophic scar fibroblasts, but not fibroblasts from non‐lesional skin sites. In addition, lapachol had no apparent effect on cell cycle and lactate dehydrogenase activity in conditioned medium from lapachol‐treated hypertrophic scar fibroblasts was nearly equal to that in medium from vehicle‐treated cells. Lapachol treatment also inhibited COL1A1 and PAI‐1 mRNA levels in hypertrophic scar fibroblasts, but did not affect IL‐6 mRNA levels. The protein levels of IL‐6 and PAI‐1 in conditioned medium from hypertrophic scar fibroblasts treated with 50 µm lapachol were lower than those from vehicle‐treated hypertrophic scar fibroblasts. Conclusions Lapachol decreased the proliferation rate of hypertrophic scar fibroblasts. As IL‐6 and PAI‐1 secretion was also lowered in lapachol‐treated hypertrophic scar fibroblasts, our findings suggested that lapachol may have suppressed extracellular matrix hyperplasia in wound healing and possibly alleviated the formation of hypertrophic scar.     

Randomized controlled trial to improve childhood immunization adherence in rural Pakistan: redesigned immunization card and maternal education

Objective A substantial dropout from the first dose of diphtheria‐tetanus‐pertussis (DTP1) to the 3rd dose of DTP (DTP3) immunization has been recorded in Pakistan. We conducted a randomized controlled trial to assess the effects of providing a substantially redesigned immunization card, centre‐based education, or both interventions together on DTP3 completion at six rural expanded programme on immunization (EPI) centres in Pakistan. Methods Mother‐child pairs were enrolled at DTP1 and randomized to four study groups: redesigned card, centre‐based education, combined intervention and standard care. Each child was followed up for 90 days to record the dates of DTP2 and DTP3 visits. The study outcome was DTP3 completion by the end of follow‐up period in each study group. Results We enrolled 378 mother–child pairs in redesigned card group, 376 in centre‐based education group, 374 in combined intervention group and 378 in standard care group. By the end of follow‐up, 39% of children in standard care group completed DTP3. Compared to this, a significantly higher proportion of children completed DTP3 in redesigned card group (66%) (crude risk ratio [RR] = 1.7; 95% CI = 1.5, 2.0), centre‐based education group (61%) (RR = 1.5; 95% CI = 1.3, 1.8) and combined intervention group (67%) (RR = 1.7; 95% CI = 1.4, 2.0). Conclusions Improved immunization card alone, education to mothers alone, or both together were all effective in increasing follow‐up immunization visits. The study underscores the potential of study interventions’ public health impact and necessitates their evaluation for complete EPI schedule at a large scale in the EPI system.