脑梗死患者血细胞间黏附分子、血小板P选择素的改变

目的　观察脑梗死患者血中性粒细胞表面细胞间黏附分子 (CD5 4 )、血小板P选择素 (CD6 2p)的变化及其临床意义。方法　用流式细胞仪测定 5 0例脑梗死患者和 2 0例健康人血中CD5 4、CD6 2p的表达水平。结果　脑梗死组CD5 4的阳性表达率为 (18 34± 8 6 5 ) % ,CD6 2p的阳性表达率为 (6 15± 3 12 ) % ,均显著高于正常对照组 (P <0 0 1) ,伴高血压脑梗死患者的二项指标分别为 (17 5 2± 7 6 8) %和 (10 16± 4 2 7) % ,均显著高于不伴高血压组和正常组 (P <0 0 5 ) ;CD6 2p与收缩压呈显著直线正相关 (r=0 716 ,P <0 0 5 )。结论　脑缺血后CD6 2p、CD5 4表达明显增高 ,但二者之间无相关性 ,提示脑缺血时两种黏附分子有不同的作用机制 ;CD6 2p与收缩压正相关 (P <0 0 5 ) ,高血压与血小板的活化有关。     

难治性抑郁症患者无抽搐电休克治疗前后注意偏向的变化

目的:探讨难治性抑郁症患者注意偏向的特点及无抽搐电休克治疗(MECT)前后的变化。方法:对28例难治性抑郁症(研究组)患者在MECT前和MECT后2、4、6、8周进行情绪图片刺激的点探测任务测试,同时选择与研究组性别、年龄及文化程度相匹配的28名健康人作为对照组,比较研究组治疗前后以及与对照组之间反应时和注意偏向分的差异。结果:研究组的平均反应时尽管MECT后较MECT前有显著缩短(P<0.05),但始终长于对照组(P均<0.05)。研究组对负性情绪图片刺激的注意偏向分尽管在MECT后显著降低(P<0.05)且后4次测量结果之间差异无统计学意义(P>0.05),但仍明显高于对照组(P<0.05)。结论:难治性抑郁症患者对负性情绪图片存在注意偏向,MECT对这种偏向可能具有改善作用。     

文拉法辛并用阿普唑仑治疗伴焦虑的抑郁症对照观察

目的　探讨文拉法辛并用阿普唑仑对伴有焦虑的抑郁症的疗效及不良反应。方法　采用随机方法将 70例患者分为文拉法辛并用阿普唑仑研究组及文拉法辛对照组 ,两组应用文拉法辛的方法及剂量相同 ,研究组合并阿普唑仑 ,疗程 6周。应用HAMD、HAMA、TESS量表 ,分别在治疗前及治疗后第 4、7、14、2 8、4 2天进行疗效及不良反应评定。结果　文拉法辛并用阿普唑仑组与文拉法辛组治疗前后HAMD总分及减分率比较差异无显著性 (P >0 .0 5 ) ,治疗后HAMA减分率研究组较对照组改变差异有显著性 (P <0 .0 1)。不良反应两组间差异无显著性 (P >0 .0 5 )。结论　文拉法辛并用阿普唑仑治疗伴有焦虑的抑郁症优于单用文拉法辛 ,并且起效更快。     

抑郁症的社会支持和防御方式研究

目的　探讨抑郁症患者应激状态、应对行为、社会支持和防御方式的临床特征。方法　采用应对行为调查表、生活环境调查表、社会支持量表和防御方式问卷 ,对 4 1例抑郁症患者进行测试 ,并与 36例正常人进行对照研究。结果　 (1)抑郁症组平均应激强度明显高于对照组 (P <0 .0 5 ) ,且抑郁症组面对应激时所采取的应对行为与对照组存在显著差异 ,主动娱乐、谋划对策、主动应付和工作投射因子分高 (P <0 .0 1) ,控制症状和消极发泄因子分低 (P <0 .0 1或P <0 .0 5 ) ;(2 )抑郁症组的社会支持满意度明显低于对照组 (P <0 .0 5 ) ,且抑郁症组对“亲属”的选用明显高于对照组 (P <0 .0 1) ;(3)抑郁症组中间型和不成熟型防御因子分高 (P <0 .0 1) ,投射、幻想、退缩因子 ,假性利他、隔离、交往倾向和消耗倾向因子分也明显高于对照组 (P <0 .0 1或P <0 .0 5 )。结论　 (1)生活事件与抑郁症状的发生可能存在直接的关系 ,且抑郁症患者面对应激更多采取外射型应对方式 ;(2 )抑郁症患者的社会支持系统满意度差 ,且防御方式存在明显的不成熟倾向。     

抗血小板药对急性脑梗死患者血小板膜糖蛋白CD62P CD63表达的调控作用

目的探讨抗血小板药对急性脑梗死患者血小板膜糖蛋白P选择素(CD62P)、溶酶体膜蛋白(CD63)表达的调控作用。方法选取2013-03—2015-04我院收治的急性脑梗死患者86例为研究对象,采用随机数表法分为观察组和对照组各43例,对照组采取阿司匹林单药治疗,观察组在此基础上联合应用氯吡格雷治疗,同时选取健康志愿者43例纳入正常组,比较3组血小板膜糖蛋白CD62P、CD63表达水平,分析观察组与对照组血小板聚集达标率、不良反应。结果治疗前观察组CD62P阳性率、CD63阳性率分别为(26.92±2.06)%、(22.15±4.19)%,对照组分别为(26.91±2.07)%、(22.15±2.18)%,2组比较无显著差异(P0.05),但均明显高于正常组(P0.05);治疗半年内观察组血小板聚集达标率93.0%明显高于对照组76.7%(P0.05);2组不良反应发生率(9.3%、4.7%)比较无显著差异(P0.05)。结论抗血小板药可有效抑制血小板活化,降低血小板膜糖蛋白表达,且不良反应轻,值得临床推广应用。     

脑卒中后抑郁症患者事件相关电位N400及其相关因素的研究

目的 探讨脑卒中后抑郁症(PSD)患者事件相关电位N400的特征及其影响因索.方法 纳入有和无PSD的脑卒中患者各85例.前者在脑卒中发病后3个月时符合中国精神障碍分类与诊断标准第3版(CCMD-3)抑郁症的诊断标准.给予PSD患者氟西汀治疗3个月.检测所有患者M00和血小板5-羟色胺(5-HT)浓度.结果 治疗前PSD患者N400的潜伏期时间和平均波幅与对照组的差异有统计学意义(P＜0.01),而血小板5-HT的浓度明显低于对照组(P＜0.01).治疗后PSD患者N400的潜伏期时间和平均波幅较治疗前分别缩短和延长(P＜0.01),血小板5-HT的浓度明显上升(P＜0.01).PSD组和对照组患者血小板5-HT浓度与N400潜伏期呈负相关(P＜0.05),而与N400平均波幅正相关(P＜0.05).结论 PSD患者N400的变化以潜伏期明显延长、平均波幅明显缩短为特征,血小板5-HT浓度影响N400的变化.     

抑郁症患者血小板五羟色胺浓度的研究

目的 通过测定抑郁症患者血小板五羟色胺（5-HT）浓度,探讨抑郁症治疗前后5-HT变化及其与临床特征的关系。方法 用高效液相色谱法（HPLC）及电化学探测仪测定60例抑郁症患者治疗前后血小板5-HT浓度,并与30名正常者对照比较,同时作相关分析。结果 治疗前后抑郁症患者血小板5-HT浓度均显著低于正常对照组（t=5．38,P〈0．001;t=3．63,P〈0．001）：治疗前血小柄5-HT浓度与HAMD因子1（焦虑／躯体化）有显著相关性（r=-0．88,P=0．001）。结论抑郁症患者血小板5-HT浓度明显降低,治疗前焦虑／躯体化症状与5-HT浓度呈负相关。     

综合护理干预措施对抑郁症患者自杀态度和自我接纳的影响

目的：探讨综合护理干预措施对抑郁症患者自杀态度和自我接纳的影响.方法选择河北省荣军医院住院的抑郁症患者78例,随机分为研究组40例和对照组38例;对照组采用精神科常规护理,研究组在此基础上实施综合性护理干预,分别在护理前及护理后4周末,采用汉密尔顿抑郁量表(HAMD)、自杀态度问卷(QSA)、自我接纳问卷(SAQ)分别评估患者的抑郁状态、自杀态度状况及自我接纳水平.结果通过综合护理干预,两组 HAMD 评分均较干预前降低,且干预组更明显(P ＜0.05);干预后研究组患者在对自杀行为性质的认识、对自杀者的态度、对安乐死的态度评分显著提高,并优于对照组(P ＜0．05);干预后研究组患者自我评价的水平显著提高,并明显优于对照组(P ＜0.05).结论心理治疗联合护理干预可以改善抑郁症患者的自杀态度和自我评价.     

利培酮合并氯丙咪嗪治疗伴强迫症状的分裂症对照研究

目的　了解利培酮合并氯丙咪嗪治疗伴强迫症状的分裂症的疗效和副反应。方法　对伴强迫症状的分裂症随机分为研究组和对照组 ,分别用利酮培合并氯丙咪嗪、氯氮平合并氯丙咪嗪治疗 8周。用PANSS、Y -BOCS评定疗效 ,用TESS评定副反应。结果　研究组治疗后PANSS、Y -BOCS总分和各因子分与治疗前比较均明显下降 (P <0 .0 1) ,与对照组相近 (P >0 .0 5 ) ;两组治疗后分裂症、强迫症状的有效率、显效率、痊愈率、总有效率、总显效率相近 (P >0 .0 5 ) ;研究组治疗后TESS总分显著低于对照组 (P <0 .0 5 )。结论　利培酮合并氯丙咪嗪治疗伴强迫症状的分裂症疗效肯定 ,副反应较轻 ,可作为治疗伴强迫症状的分裂症的一个较好选择     

米氮平联合CCBT治疗轻中度抑郁症的效果及对生活质量的影响

目的探讨米氮平联合计算机化认知行为治疗(CCBT)对轻中度抑郁症的效果及对患者生活质量的影响,为轻中度抑郁症的心理治疗提供参考。方法选取96例符合《精神障碍诊断与统计手册(第5版)》(DSM-5)诊断标准的轻中度抑郁症患者,采用随机数字表法分为研究组和对照组各48例,对照组给予米氮平,研究组在米氮平治疗基础上联合CCBT,两组均治疗12周。于治疗前及治疗2、4、6、12周后采用汉密尔顿抑郁量表17项版(HAMD-17)评定患者抑郁症状及疗效,治疗前后采用世界卫生组织生存质量评定量表简表(WHOQOL-BREF)评定生活质量,治疗期间采用副反应量表(TESS)评定安全性,治疗12周后采用Morisky治疗依从性问卷(MMAS-8)评定治疗依从性。结果治疗12周末,研究组HAMD-17评分均低于对照组(P均0. 05)。研究组WHOQOL-BREF的生理领域、心理领域、社会关系领域、环境领域、总体健康状况、总体生活质量评分均高于对照组(Р均0. 01)。治疗后研究组治疗依从性高于对照组(P0. 05)。结论米氮平联合CCBT对轻中度抑郁症的效果及对患者生活质量的影响优于单用米氮平治疗。     

Platelet–leukocyte interaction and platelet activation in migraine: a link to ischemic stroke?

OBJECTIVES: Migraine has been identified as an independent risk factor for ischemic stroke. Both neurogenic inflammation and platelet activation have been linked to the pathophysiology of migraine. Increased platelet activation results in up-regulation of specific binding to leukocytes which promotes pro-inflammatory leukocyte secretion and their tethering to endothelium, a mechanism that has been demonstrated in stroke and which could provide a link to migraine. We aimed to determine whether platelet-leukocyte aggregation is increased in migraine patients outside an acute attack. METHODS: Seventy two patients with migraine according to IHS criteria were compared to a control group (n = 72). Whole blood flow cytometry was used to quantify the activation dependent P selectin on the platelet, and to assess the fraction of platelets bound to the different leukocyte subsets. RESULTS: Migraine patients showed significantly more platelet-leukocyte aggregates compared to the control subjects (p = 0.003). This effect was driven by an increased polymorphonuclear cell-platelet aggregation (p = 0.003) whereas platelet aggregation with monocytes and lymphocytes was not. Platelet activation was also increased (p = 0.001). CONCLUSIONS: In migraine pro-inflammatory platelet adhesion to leukocytes occurs during the headache free interval similar to that seen in acute coronary and cerebrovascular syndromes. This may suggest a link between migraine and stroke on a cellular level.     

Increased platelet surface expression of P-selectin and thrombospondin as markers of platelet activation in essential thrombocythaemia

Essential thrombocythaemia (ET) is a clonal myeloproliferative disorder associated with an increased risk of both thromboembolic and bleeding complications. Platelet activation plays a crucial role in the pathogenesis of prethrombotic conditions. The platelet surface expression of p-selectin (CD62p) and thrombospondin (TSP) has been shown to correlate with platelet activation. In the present study, we used a flow cytometric assay to study whether the fraction of platelets expressing CD62p and TSP is increased in newly diagnosed ET. Thirty-four patients with newly diagnosed ET and 25 healthy control subjects were investigated. The proportion of platelets expressing the activation-dependent antigens CD62p and TSP was higher in patients with ET (CD62p: 14.7+/-15.0%; TSP: 12.4+/-9.9%) as compared with healthy control subjects (CD62p: 3.0+/-4.0%; TSP: 3.2+/-3.2%; p< 0.001). In ET, there was a linear correlation between platelet surface expression of CD62p and TSP (p<0.0001, r=0.83). At diagnosis of ET, 20 patients were symptomatic and 14 asymptomatic. Compared with asymptomatic ET patients there was no difference in the expression of CD62p (18.3+/-16.2% vs. 14.5+/-13.4%) and TSP (14.4+/-9.8% vs. 12.8+/-9.5%) in symptomatic ET patients. In conclusion, increased expression of platelet neoantigens is present at the diagnosis of ET. Both activation-dependent epitopes CD62p and TSP are increasingly expressed on the platelet surface in newly diagnosed ET patients.     

Platelet activation biomarkers in Berkeley sickle cell mice and the response to prasugrel

Vaso-occlusive crisis (VOC) is a common complication that occurs in sickle cell disease (SCD) patients. Although underlying mechanisms of VOC remain unclear, platelet activation has been associated with VOC. In the present study, plasma adenine nucleotide measurements using LC-ESI-MS/MS showed that plasma ADP in the Berkeley murine model of SCD was significantly higher (applox. 2.7-fold increase) compared with control mice. Assessment of platelet activation markers using flow cytometry indicated that in SCD mice at steady state (8 weeks old), circulating platelets were partially activated and this tended to increase with age (15 weeks old). The administration of prasugrel, a thienopiridyl P2Y₁₂ antagonist, did not affect the activation state of circulating platelets suggesting P2Y₁₂ independent mechanism of activation. In this murine SCD model, ex vivo addition of ADP or PAR4 TRAP resulted in further platelet activation as assessed by expression of activated GPIIb/IIIa and P-selectin both at 8 and 15 weeks. In 15 weeks old SCD mice, agonist-induced increases in activation markers were enhanced compared to control mice. Oral administration of prasugrel effectively inhibited ex vivo platelet activation consistent with clinical data in patients with SCD. In conclusion, in the Berkeley murine model of SCD, we found evidence of basal and agonist-stimulated platelet activation which could in part be attenuated by prasugrel. These data are consistent with observations made in patients with SCD and suggest possible utility of this murine model and prasugrel therapy in exploring treatment options for patients with SCD.     

The influence of the pulsatility of the blood flow on the extent of platelet adhesion

A new improved flow system was developed to study the influence of blood flow pulsatility on platelet adhesion on adhesive proteins and bio-medical materials. The pulsatility was introduced by changing the shear rate every 15 s in blood that was aspirated through a perfusion chamber by a syringe pump. The advantage of this new system is that it avoids system related platelet activation. At steady low shear rate (300/s) after 5 min a collagen type III surface was covered for 24.2 ± 3.8% with platelets. At steady high shear rate (1300/s) platelet coverage to collagen was 48.8 ± 6.8%. When pulsatility was introduced by changing the shear rate was every 15 s form 300/s to 1300/s and vice-versa, platelet coverage after 5 min was increased to 60.4 ± 4.0% (p < 0.001). After 5 min perfusion samples were taken from the perfusate and the extent of platelet activation was measured. The significant difference in surface expression of P-selectin on platelets is only seen when comparing pulse flow with control (no flow). We concluded that a significant increase in platelet activation during blood pulsatile flow compared with steady flow, which results in an increased platelet adhesion to collagen.     

Circulating activated platelets in myeloproliferative disorders.

Platelet activation in patients with myeloproliferative disorders is often suggested by increased platelet alpha-granule secretion and an acquired storage pool defect of dense granules. To determine whether activated platelets circulate in patients with chronic myeloproliferative disorders, we evaluated the binding of monoclonal antibodies against activation-dependent epitopes on resting platelets (P 12, CD 63, and CD 62) in 12 patients with prominent megakaryocytic proliferation (8 patients with essential thrombocythemia, 2 with chronic myeloid leukemia, and 2 patients with polycythemia rubra vera). In addition, platelet aggregation in response to collagen, adenosine diphosphate, platelet activating factor, and agglutination with ristocetin was investigated. In 3 patients there was an increased percentage of platelets binding at least 1 activation marker. In 2 other patients, a trend towards increased antibody binding was observed. Binding of the antibody to thrombospondin (P 12) was related to expression of the GMP 140 protein (CD 62, r = 0.76, p = 0.004). There was no correlation of platelet aggregation defects in vitro to increased expression of platelet activation markers or to thrombohaemorrhagic complications. However, circulating activated platelets were detected in three out of five patients with a history of bleeding or thrombotic complications. The results of this preliminary study suggest that some but not all patients with myeloproliferative disorders showed increased amounts of circulating activated platelets. The relation of bleeding and thrombotic complications to the expression of activation-dependent epitopes on platelets in myeloproliferative disorders requires further investigation.     

Increased leukocyte-platelet adhesion in patients with graft occlusion after peripheral vascular surgery

Graft occlusion following peripheral vascular surgery is attributable to some combination of acute thrombosis, and progression of atherosclerosis: interactions between leukocytes and activated platelets may play a role in both of these processes. This investigation measured perioperative leukocyte-platelet conjugate formation, and leukocyte and platelet activation in 46 patients undergoing surgery for lower extremity peripheral vascular disease (PVD). All patients were followed for graft patency over the next 6 months; 27 patients had grafts that remained patent while 19 had graft occlusion. On postoperative day #1 (POD#1), the graft occlusion group demonstrated a significantly greater increase in circulating levels of both monocyteplatelet and neutrophil (PMN)-platelet conjugates compared to the patent graft patients (p=0.015 and 0.018, respectively). PMN activation, assessed by increases in surface CD11b expression, was also significantly increased on POD#1 in the graft occlusion group compared to the patent group (p=0.026). The percentage of circulating activated (CD62P+) platelets did not differ between groups, but patients with graft occlusion demonstrated a higher percentage of younger, reticulated plate-lets throughout the study period (p=0.008), indicating increased platelet turnover. We conclude that in the early postoperative period, leukocyte-platelet adhesion, PMN activation, and platelet turnover are significantly greater in PVD patients who go on to develop later graft occlusion. Cellular activation and heterotypic cell interactions in peripheral vascular surgery patients may be important in the etiologies of thrombosis and/or accelerated atherosclerosis leading to graft loss.     

Regulation of CD40L (CD154) and CD62P (p-selectin) Surface Expression upon GPIIb-IIIa Blockade of Platelets from Stable Coronary Artery Disease Patients

Introduction

The aim of this study was to further characterize the effect of the antiplatelet agents, aspirin and eptifibatide, on the surface expression of CD40L and CD62P on platelets from patients with stable coronary artery disease.

Materials and methods

Platelet function was evaluated using standard light transmission aggregometry. Measurements of CD62P and CD40L were carried out by flow cytometry and ELISA assays.

Results

All patients had the expected level of platelet aggregation inhibition in response to 20 μM ADP in the presence of increasing eptifibatide concentrations. Platelet activation by adenosine diphosphate (ADP) or thrombin agonist peptide (TRAP) increased CD62P and CD40L surface density in the presence of aspirin by 1.9 - 2.8 -fold. Aspirin treatment did not prevent either CD62P or CD40L expression. Eptifibatide pretreatment at pharmacologically relevant concentrations blocked agonist-induced increases in CD62P platelet surface density. A marked percentage of platelets still expressed low levels of surface CD62P suggesting slight platelet activation even with potent platelet inhibition. Eptifibatide also blocked agonist-induced increases in CD40L surface expression and decreased the percent of platelets positive for surface CD40L. Decreased expression of CD40L was due to an inhibition of CD40L translocation and not caused by enhanced shedding from the surface, as soluble CD40L (sCD40L). Eptifibatide concentrations that effectively blocked platelet aggregation correlated with total inhibition of increased CD62P and CD40L surface density.

Conclusion

Blockade of the GPIIb-IIIa receptor on platelets from coronary artery disease patients may have significant bearing on reducing proinflammatory and procoagulant events mediated by CD62P and sCD40L.     

Expression of stromal‐cell‐derived factor‐1 (SDF‐1): a predictor of ischaemic stroke?

Background and purpose: Platelet stromal‐cell‐derived factor‐1 (SDF‐1) plays a pivotal role in angiogenesis and the regeneration of ischaemic tissue through the regulation of haematopoietic progenitor cells and is upregulated at the sites of vascular injury and platelet activation. Thus, SDF‐1 has recently been discussed as a predictor in ischaemic diseases such as acute myocardial infarction. However, no clinical data pertinent to the investigation of the platelet SDF‐1 expression in patients with stroke are available. Methods: We consecutively evaluated 196 patients who were admitted to the stroke unit with symptoms suspected for stroke. Surface expression of the platelet activation markers (P‐selectin and GPIb) and the expression of platelet‐bound SDF‐1 were determined by two‐colour whole blood flow cytometry. Results: Patients with transient ischaemic attack (TIA) as well as with ischaemic stroke showed similar levels of SDF‐1 expression on hospital admission compared with patients with non‐ischaemic (NI) events and with 30 healthy controls (TIA (mean fluorescence intensity ± SD): 31.5 ± 18.2 vs. NI: 26.4 ± 15.7; P = 0.361; stroke: 28.7 ± 19.8 vs. NI; P = 0.943; control: 26.1 ± 11.3; P > 0.05 compared with all). Platelet SDF‐1 expression showed a trend with the severity of stroke according to National Institute of Health Stroke Scale score (r = 0.125; P = 0.085), but significantly correlated with the peak levels of C‐reactive protein (r = 0.218; P = 0.002) and with the levels of platelet activation (P‐selectin: r = 0.389; P = 0.001). Multifactorial analysis of covariance revealed a significant influence on platelet SDF‐1 expression by smoking (P = 0.019). Conclusions: Platelet SDF‐1 surface expression did not show any significant difference in patients with TIA and ischaemic stroke compared with patients with NI events. Thus, single biomarker evaluation of platelet SDF‐1 surface expression is not helpful to predict ischaemic stroke.     

Major depression induces oxidative stress and platelet hyperaggregability

We have previously demonstrated an impairment of intraplatelet l-arginine-nitric oxide-cGMP pathway in major depression (MD) associated to platelet dysfunction. Here, we evaluated arginase pathway and phosphodiesterase 5 (PDE5) expression in platelets, systemic and intraplatelet oxidative status in untreated MD patients, and their effects on platelet aggregation. Blood samples were collected from 22 treatment naive MD patients (31 ± 2 yr) and 27 healthy subjects (33 ± 2 yr). MD patients presented with an activation of platelet arginase II, which competes with l-arginine for the production of nitric oxide (NO). An increase in protein carbonylation, overexpression of NADPH oxidase and PDE5, an enzyme that inactivates cGMP, was observed in platelets from MD patients compared to controls. In this context, platelet hyperaggregability was found in MD patients. On the other hand, antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase activities in serum and in platelets did not differ between groups. The increased activation of intraplatelet arginase and platelet aggregability, in addition to an overexpression of PDE5 and oxidative stress may contribute to alterations in l-arginine–NO–cGMP pathway and in platelet function, and consequently to the increased thrombotic risk in MD.     

The novel P2Y12 antagonist AZD6140 rapidly and reversibly reduces platelet activation in diabetic rats

Introduction

Excessive platelet activation fundamentally contributes to cardiovascular events and mortality in patients with diabetes mellitus. Functional resistance has been described for current antiplatelet therapies in broad populations that include patients with diabetes. We investigated acute and chronic effects of AZD6140, a reversible oral rapid-onset P2Y₁₂ antagonist, on platelet reactivity in diabetic rats.

Materials and Methods

Diabetes was induced by streptozotocin injection in male Wistar rats. After 4 weeks, AZD6140 was administered (5 mg/kg by gavage) and achieved sufficient plasma levels within 30 minutes. Platelet reactivity was determined by ADP-induced P-selectin expression, aggregation and adhesion on fibrinogen coated membranes under arterial flow conditions.

Results

At 0.5 hour, AZD6140 strongly reduced ADP-induced P-selectin surface expression, inhibited ADP-induced platelet aggregation, and significantly reduced platelet adhesion to fibrinogen under arterial flow conditions. Chronic treatment with AZD6140 (10 mg/kg bid for 2 weeks, based on data obtained in the acute study) starting at day 14 reduced P-selectin surface expression on circulating platelets, indicating lower in vivo platelet activation. Platelet reactivity was improved 12 hours after the last dose, while basal platelet activity remained reduced. AZD6140 was rapidly absorbed in diabetic rats and inhibited platelet reactivity. Chronic treatment lowered in vivo platelet activation of circulating platelets.

Conclusion

AZD6140 inhibits platelet reactivity in diabetic rats rapidly and reversibly. Markers of tonic platelet activation, which were increased in diabetic rats, were lowered to levels comparable to non-diabetic rats following chronic treatment with AZD6140.