哒嗪酮类新化合物9612的抗血小板聚集作用

研究了新型哒嗪酮类化合物 96 12对家兔和大鼠血小板聚集的影响 .结果发现 ,96 12在体外能明显抑制花生四烯酸 (AA) ,腺苷二磷酸 (ADP)和凝血酶 (thrombin)诱导的家兔血小板聚集 ,其IC50 分别为 3 2 0 ,9 44和 7 10 μmol/L .96 12 .灌胃给药 (ig) ,能显著抑制AA和ADP诱导的大鼠血小板聚集 ,其作用与同等剂量 (15 0mg/kg)的阿斯匹林 (ASA)相比无明显差异 (P >0 0 5 ) .     

二氢哒嗪酮类化合物的研究进展

血栓形成性疾病及其并发症已成为损害人类生命和健康的重要原因。二氢哒嗪酮类化合物具有重要的强心、抗血小板聚集作用,其药理活性十分显著。现对该类化合物近年来的进展进行简要的综述。     

苯并咪唑-哒嗪酮类化合物的设计与合成及其抗血小板聚集活性

以具有抗血小板聚集活性的苯并咪唑类化合物和哒嗪酮类化合物为先导化合物 ,运用药物化学的拼合原理 ,设计并合成了 6个新的苯并咪唑 哒嗪酮类化合物及 6个新的苯并咪唑 苯并哒嗪酮类化合物 ,并经NMR和MS进行了结构鉴定 ,对其进行了抗血小板聚集的药理活性筛选。结果表明所合成目标化合物基本无抗血小板聚集活性     

二氢哒嗪酮类化合物的合成及其对血小板聚集的抑制作用

根据二氢哒嗪类化合物的抗血小板聚集活性的构效关系，设计合成了１８个６－（４－取代酰胺基苯基）－４，５－二氢－３（２Ｈ）－哒嗪酮类化合物，均为首次报道，所有目标化合物在体外对ＡＤＰ诱导的兔血小板聚集均有不同程度的抑制作用，其中５－甲基哒嗪酮类化合物的抑制作用较强。     

6-取代二氢哒嗪酮类化合物的合成及血小板聚集抑制作用

In order to develop more potent and less toxic, antithrombotic agents, ten 6-(4-substituted piperazinyl acetyl aminophenyi)-4, 5-dihydro-3(2H)-pyridazinones were synthesized. The title compounds were tested in vitro for platelet aggregation inhibitory activity with ADP-induced rat platelets and PAF-induced rabbit platelets. Preliminary tests showed that all of the pyridazinones could inhibit ADP-induced rat platelet aggregation. Ⅰ₇, Ⅰ₈, Ⅰ₉ were more potent than the control compound CI 930. Ⅰ₉ was the most potent compound with IC₅₀ of 0.99 μmol/L. Pertaining to PAF-induced rabbit platelet aggregation. Ⅰ₉ was the most potent inhibitor with IC₅₀ of 3.7 μmol/L.     

6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其抑制血小板聚集的作用

为了寻找较理想的抗血栓药物,本文设计合成了6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物16个。对ADP诱导的大鼠体外血小板聚集,均有不同程度的抑制作用。其中,化合物Ⅱ₂,Ⅱ3和Ⅱ₄的作用大于CCI-17810,又以Ⅱ₄的作用为最强。     

6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其抑制血小板聚集的作用

为了寻找较理想的抗血栓药物,本文设计合成了6-(4-取代苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物16个。对ADP诱导的大鼠体外血小板聚集,均有不同程度的抑制作用。其中,化合物Ⅱ_2,Ⅱ3和Ⅱ_4的作用大于CCI-17810,又以Ⅱ_4的作用为最强。     

哒嗪酮类化合物的药用研究近况

简要综述哒嗪酮类化合物近年来的药用研究进展.哒嗪酮类化合物具有多种重要的生物活性,根据作用机制的不同,可分为钙增敏剂、磷酸二酯酶抑制剂、环氧合酶抑制剂等,并可用于相关疾病的治疗.     

哒嗪酮类化合物的合成及其对血小板聚集的抑制作用

为了寻找高效的抗血栓药物而设计合成了２２个６-（４-取代苯基）-５-甲基-４，５-二氢-３（２Ｈ）-哒嗪酮类新化合物，对ＰＡＦ引起的兔血小板聚集有不同程度的抑制作用，其中有１１个化合物的作用比先导化合物（１）强，最强的为（１０），其ＩＣ５０为０．５８μＭ，对ＡＤＰ诱导的兔血小板聚集的抑制作用也以（１０）最强，其ＩＣ５０为０．６９μＭ。     

6-(4'-取代酰胺基苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其抑制血小板聚集作用

目的：６（４′取代苯基）４,５二氢３（２Ｈ）哒嗪酮类化合物的合成及抗血小板聚集活性的研究。方法：通过付克反应、碳链延长、水解和环合反应得到两个关键中间体,然后通过酰化反应制得各种酰胺化合物;参考Ｂｏｒｎ比浊法测定目标化合物的抗血小板聚集活性。结果：设计合成了２４个６（４′取代酰胺基苯基）４,５二氢３（２Ｈ）哒嗪酮类化合物,２２个为首次报道;所有化合物在体外对ＡＤＰ诱导的兔血小板聚集均有不同程度的抑制作用,第ＩＩ类化合物的抑制作用强于第Ｉ类化合物,其中Ｉ１,Ｉ３,ＩＩ１,Ｉ３,ＩＩ４,Ｉ６和ＩＩ９的抑制作用均强于对照药ＣＩ９３０,其中Ｉ１和ＩＩ３的抑制作用最强,其ＩＣ５０约为ＣＩ９３０的１／１０。结论：其中一些化合物显示较强的抗血小板聚集活性,值得进一步研究。     

低分子肝素的抗血栓作用

研究了低分子肝素 (lowmoleculerweightheparin ,LMWH)的抗血栓作用 .研究表明 ,静脉注射LMWH (40 0、2 0 0IU/kg)能明显降低家兔高、中、低切比粘度 (P <0 .0 1) ,并显著降低家兔体内实验性血栓湿重及干重 (P <0 .0 0 1) ;静脉注射LMWH 40 0、2 0 0IU/kg及 30 0、15 0IU/kg能分别抑制家兔及小鼠ADP诱导的血小板聚集作用 (P <0 .0 0 1) .实验证明 ,相对分子质量为 6 40 0的低分子肝素有抗血栓作用 .     

Antithrombotic strategies for preventing long-term major adverse cardiovascular events in patients with non-valvular atrial fibrillation who undergo percutaneous coronary intervention

Introduction: Balancing the risk of recurrent ischemia and bleeding among patients with non-valvular atrial fibrillation who undergo percutaneous coronary intervention (PCI) is challenging. Postprocedural antithrombotic therapy aims to reduce the risk related to coronary artery disease, stent placement, and atrial fibrillation, with acceptable risks of bleeding.

Areas covered: This review summarizes evidence and recommendations related to long-term antithrombotic strategies in such patients. An overview of the findings from recent meta-analyses and select observational studies is provided, and important completed and ongoing randomized trials are described in detail. Recommendations pertaining to treatment intensity and duration, including the choice of specific anticoagulant and antiplatelet agents, are given.

Expert opinion: Triple therapy (oral anticoagulation with dual antiplatelet therapy) is associated with an increased bleeding risk compared with double therapy (oral anticoagulation with a single antiplatelet agent), but double therapy does not appear to be associated with an increased risk of recurrent ischemia or death. Completed trials make a compelling case for double therapy with clopidogrel, not aspirin, when compared with full-intensity triple antithrombotic therapy. We believe that double therapy with an anticoagulant and clopidogrel should generally be favored instead of triple antithrombotic therapy.     

Antithrombotic effects of Huanglian Jiedu decoction in a rat model of ischaemia-reperfusion-induced cerebral stroke

ContextHuanglian Jiedu Decoction (HLJJD) has a variety of pharmacological activities, such as anti-inflammatory and neuroprotection against ischaemic brain injury.ObjectivesThis ex vivo study explores its antithrombosis activity and inhibition of platelet aggregation.Material and methodsTo study the antithrombosis activity of HLJJD ex vivo, saline, or HLJDD (100, 200, and 500 mg/kg) was treated prophylactically by gavage for 3 days in Wistar rats (n = 4). Based on the rat model of transient middle cerebral artery infarction (MCAO) or normal rats (n = 4), the antithrombotic activity in the normal group and HLJDD subgroups on prothrombin time, thrombus weight, platelet aggregation, and others was evaluated, followed by the antiplatelet aggregation of its main components (n = 4).ResultsThe weight of the thrombus increased significantly at 24 h after MCAO onset. HLJJD did not influence the change of PT, but significantly inhibited thrombosis by 12.5, 20.0, and 20.5% in reducing the dry weight of thrombus, and blocked collagen-induced platelet aggregation by 25.5, 39.0, and 42.7% and adhesion of blood platelet by 17.3, 26.2, and 27.3%. The IC₅₀ value of HLJJD on collagen-induced platelet aggregation was 670 mg/kg. Geniposide only facilitated antiplatelet aggregation induced by collagen, but not AA or ADP. Both baicalin and berberine showed markedly antiplatelet aggregation induced by all activators. The antithrombotic activity of baicalin was relatively higher than that of berberine (35.0–47.8% vs. 20.6–33.5%).ConclusionOur results indicated that HLJDD regulated blood circulation by inhibiting platelet aggregation and thrombosis, which might also extensively contribute to the clinical prevention and treatment of cerebrovascular diseases.     

6-(4-取代酰胺基苯基)-4,5-二氢-3(2H)-哒嗪酮类化合物的合成及其对血小板聚集的抑制作用

设计合成了１８个６（４取代酰胺基苯基）４，５二氢３（２Ｈ）哒嗪酮类化合物，其中１６个为首次报道．用两种方法合成了中间体６（４氨基苯基）５甲基４，５二氢３（２Ｈ）哒嗪酮．所有化合物体外对ＡＤＰ诱导的兔血小板聚集均有不同程度的抑制作用，５甲基取代的化合物大多具有较强的抑制作用，其中（９），（１０），（１１），（１６），（１７）和（１８）的抑制作用均强于对照物ＣＩ９３０，其抑制作用约为ＣＩ９３０的２～５倍．     

莲心碱对血小板聚集、凝血功能和血栓形成的影响

目的探讨莲心碱对大鼠体内血小板聚集和凝血功能的影响,同时评价其抗血栓作用。方法以二磷酸腺苷(ADP)诱导血小板聚集,采用比浊法观察莲心碱对大鼠体内血小板1、5min聚集率和最大聚集率的影响;通过毛细管法和减尾法分别研究莲心碱对小鼠凝血时间和尾出血时间的影响,同时评价莲心碱对大鼠凝血酶原时间(PT)、活化部分凝血激酶时间(APTT)及凝血酶时间(TT)的影响;采用Chandler法及动静脉旁路模型研究莲心碱对大鼠体外血栓和动静脉旁路血栓形成的影响。结果莲心碱5mg·L-1和10mg·L-1均能明显抑制ADP诱导的大鼠体内血小板1、5min聚集率和最大聚集率;明显延长大鼠PT、APTT和TT;明显延长小鼠凝血时间及尾出血时间;不同程度抑制大鼠体外血栓和动静脉旁路血栓形成,减轻血栓湿重和干重。结论莲心碱可明显对抗血栓形成,并具有对抗血小板聚集和凝血作用。     

血小板激活因子和银杏内酯B对洗涤兔血小板中cAMP含量的影响

研究了血小板激活因子(PAF)和PAF拮抗剂银杏内酯B对洗涤兔血小板中cAMP含量的作用. 结果表明PAF(0.1-1.0 μmol·L^-1)对血小板的基础cAMP水平无影响, 但对前列腺素E₁(PGE₁) 2 μmol·L^-1及4,5-二氢-6-［4-(1H-咪唑-1)苯基］-5-甲基-3-(2H)-哒嗪酮(CI-930) 20 μmol·L^-1引起的cAMP升高有显著的抑制作用. 银杏内酯B能完全拮抗PAF抑制PGE₁和CI-930升高cAMP的作用, IC₅₀分别为4.7和12.5 μmol·L^-1. 合用磷酸肌酸/磷酸肌酸激酶和阿司匹林对PAF和银杏内酯B的作用均无影响. 提示PAF对磷酸二酯酶的激活作用及腺苷酸环化酶的抑制作用是PAF的直接作用，与其同PAF受体结合有关.     

Effects of platelet activating factor and ginkgolid B on the cAMP levels in washed rabbit platelets

研究了血小板激活因子（ＰＡＦ）和ＰＡＦ拮抗剂银杏内酯Ｂ对洗涤兔血小板中ｃＡＭＰ含量的作用．结果表明ＰＡＦ（０．１－１．０μｍｏｌ·Ｌ－１）对血小板的基础ｃＡＭＰ水平无影响，但对前列腺素Ｅ１（ＰＧＥ１）２μｍｏｌ·Ｌ－１及４，５－二氢－６－［４－（１Ｈ－咪唑－１－）苯基］－５－甲基－３－（２Ｈ）－哒嗪酮（ＣＩ－９３０）２０μｍｏｌ·Ｌ－１引起的ｃＡＭＰ升高有显著的抑制作用．银杏内酯Ｂ能完全拮抗ＰＡＦ抑制ＰＧＥ１和ＣＩ－９３０升高ｃＡＭＰ的作用，ＩＣ５０分别为４．７和１２．５μｍｏｌ·Ｌ－１．合用磷酸肌酸／磷酸肌酸激酶和阿司匹林对ＰＡＦ和银杏内酯Ｂ的作用均无影响．提示ＰＡＦ对磷酸二酯酶的激活作用及腺苷酸环化酶的抑制作用是ＰＡＦ的直接作用，与其同ＰＡＦ受体结合有关．     

小檗碱抗富含血小板血浆凝块收缩的作用及其机制

对小檗碱抗富含血小板血浆凝块收缩的作用进行研究，结果表明①小檗碱（ＢＲ）浓度为０．２９～０．８７ｍｍｏｌ·Ｌ－１时．有非常显著的抑制凝块收缩的作用。②ＢＲ浓度为０．５～２．０ｍｍｏｌ·Ｌ－１时．对血小板ｃＡＭＰ水平无影响．提示ＢＲ抑制凝块收缩的作用与ｃＡＭＰ无关．③当外加Ｃａ２＋浓度自０增加到１１．４７ｍｍｏｌ·Ｌ时，凝块收缩率随Ｃａ２＋内流增加而上升。同样条件下．ＢＲ浓度自０增加到０．６ｍｍｏｌ·Ｌ－１时．凝块收缩率显著或非常显著地下降。提示ＢＲ抑制凝块收缩的机制可能是由于直接抑制了Ｃａ２＋内流所致。     

Thrombolytic activity of YM866, a novel modified tissue-type plasminogen activator,in a rabbit model of jugular vein thrombosis

The thrombolytic activity of a novel modified t-PA analog, YM866, was compared with that of recombinant t-PA (t-PA) in rabbits with experimental jugular vein thrombosis. Thrombus was induced in an isolated segment of the jugular vein from a mixture of whole autologous blood and thrombin. Thirty minutes after the induction of thrombus, YM866 was administered by iv bolus injection, while t-PA was given by the same method or by a 60-min iv infusion. Thrombi were removed 70 min after iv bolus injection or 10 min after the termination of iv infusion, and thrombus size was measured by total protein content in the isolated thrombus. Both YM866 and t-PA exhibited dose-dependent thrombolysis; the thrombolytic activity of YM866, however, was 4 times greater than that of t-PA. The improved thrombolytic activity of YM866 correlated with its relatively higher antigen levels in plasma, which result from its prolonged biological half-life. Depletion of plasma fibrinogen to less than 20% of baseline levels was observed in all groups. Template bleeding time was not significantly altered in any group. These results suggest that YM866 offers the potential for clinical use in thrombolytic therapy by iv bolus injection for patients with venous thromboembolic diseases. © 1994 Wiley-Liss, Inc.