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新型血小板一氧化氮供体(LA816)、阿司匹林、氯吡格雷及联合治疗对猪离体模型中血流和损伤依赖性血栓形成的抑制作用。

Effects of a novel platelet nitric oxide donor (LA816), aspirin, clopidogrel, and combined therapy in inhibiting flow- and lesion-dependent thrombosis in the porcine ex vivo model.

作者信息

Vilahur Gemma, Segalés E, Salas E, Badimon L

机构信息

Cardiovascular Research Center, Institut Català de Ciències Cardiovasculars-Consejo Superior de Investigaciones Científicas, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.

出版信息

Circulation. 2004 Sep 21;110(12):1686-93. doi: 10.1161/01.CIR.0000142296.19558.99.

Abstract

BACKGROUND

Acetylsalicylic acid (ASA), or aspirin, plus clopidogrel is becoming the standard antithrombotic treatment in people with coronary disease. Novel approaches such as the use of platelet-selective nitric oxide (NO) donors may provide additional protection against thrombosis. We evaluated the antithrombotic properties of a novel platelet-selective NO donor (LA816) administered alone and in combination with ASA, clopidogrel, or ASA+clopidogrel.

METHODS AND RESULTS

Thrombogenicity was measured in the porcine experimental model and assessed as platelet-thrombus formation in the ex vivo Badimon perfusion chamber. Pigs were randomly divided into 4 groups: (1) placebo control, (2) clopidogrel, (3) ASA, and (4) ASA+clopidogrel (ASA and clopidogrel were given orally, 10 mg x kg(-1) x d(-1) for 3 d). The animals were anesthetized, heparinized, and catheterized, and the Badimon perfusion chamber was placed in an extracorporeal shunt. After baseline perfusions, all animal groups received the intravenous infusion of LA816 for 2 hours. Platelet aggregation, blood pressure, and heart rate also were evaluated during the experiments. LA816, clopidogrel, and ASA+clopidogrel produced a reduction of approximately 45% on thrombus mass versus placebo control perfusions (P<0.05). Combined treatment of oral ASA+clopidogrel and intravenous LA816 produced a significant further reduction of 25% in platelet deposition (70% from placebo controls; P<0.0001). LA816 intravenous treatment did not modify blood pressure or heart rate.

CONCLUSIONS

Acute NO donation with LA816, without modifying hemodynamic parameters, provides the same inhibitory effect as that obtained with chronic treatment with clopidogrel+ASA. Moreover, LA816 provides platelet inhibitory effects in addition to those of the combined blockade of cyclooxygenase and P2y(12) receptor.

摘要

背景

乙酰水杨酸(ASA),即阿司匹林,联合氯吡格雷正成为冠心病患者的标准抗栓治疗方案。使用血小板选择性一氧化氮(NO)供体等新方法可能提供额外的抗血栓形成保护。我们评估了一种新型血小板选择性NO供体(LA816)单独使用以及与ASA、氯吡格雷或ASA +氯吡格雷联合使用时的抗栓特性。

方法与结果

在猪实验模型中测量血栓形成性,并在体外Badimon灌注室中评估血小板血栓形成情况。猪被随机分为4组:(1)安慰剂对照,(2)氯吡格雷,(3)ASA,以及(4)ASA +氯吡格雷(ASA和氯吡格雷口服给药,10 mg·kg⁻¹·d⁻¹,共3天)。动物麻醉、肝素化并插管,将Badimon灌注室置于体外分流中。在基线灌注后,所有动物组静脉输注LA816 2小时。实验期间还评估了血小板聚集、血压和心率。与安慰剂对照灌注相比,LA816、氯吡格雷和ASA +氯吡格雷使血栓质量减少约45%(P<0.05)。口服ASA +氯吡格雷与静脉注射LA816联合治疗使血小板沉积进一步显著减少25%(比安慰剂对照减少70%;P<0.0001)。静脉注射LA816治疗未改变血压或心率。

结论

LA816急性给予NO,在不改变血流动力学参数的情况下,提供了与氯吡格雷 + ASA长期治疗相同的抑制作用。此外,LA816除了对环氧合酶和P2y(12)受体联合阻断的作用外,还具有血小板抑制作用。

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