联合应用噻氯匹啶与阿司匹林治疗不稳定型心绞痛的疗效观察

不稳定型心绞痛发生机制常为动脉粥样硬化斑块破裂或腐蚀导致血栓形成 ,噻氯匹啶与阿司匹林是目前临床常用的 2种重要抗血小板药物。噻氯匹啶对肾上腺素、二磷腺苷 (ＡＤＰ)、凝血酶、ＴＸＡ2 、胶原苷诱导的血小板聚集均有强烈的抑制作用。噻氯匹啶尚能抑制血小板黏附和ＡＤＰ介导的血小板腹颗粒 ,抑制ＡＤＰ诱发的血小板上糖蛋白Ⅱｂ/Ⅲａ受体暴露。阿司匹林通过使环氧化酶乙酸化而失活 ,从而使ＴＸＡ2 和前列环素 (ＰＧＥ2 )合成均减少。我科于1999～ 2 0 0 1年应用噻氯匹啶与阿司匹林合用治疗不稳定型心绞痛 35例。现报告如下。1　材料…     

噻氯匹定对血浆蛋白原的影响

噻氯匹定(ticlopidine,坻克力得、力抗栓)是一种血小板功能抑制剂.近年来随着对脑卒中治疗方法和药物的研究,对人体凝血机制以及抗凝机理的研究也日益增加,新型抗凝血药也在不断地被开发应用.噻氯匹定是一种比较新的抑制血小板功能的药物.临床用药表明,该药可明显延长凝血时间,发挥抗凝作用.但噻氯匹定对脑卒中患者血浆纤维蛋白原的影响尚未见国内有报道.我们通过41例脑卒中患者服用该药前后各项实验指标的观察,探讨噻氯匹定的抗凝机制.l 材料与方法1.1 仪器 血液凝固分析装置(日本东亚医用电子株式会社制造);Cell-DYN-1400(美国贝克曼公司制造).1.2 药品 盐酸噻氯匹定(法国产,批号为0295 067,剂量为0.25mg).     

补阳还五汤及有效组分生物碱和苷对大鼠血小板聚集及血小板环核苷酸的影响

目的探讨补阳还五汤及其有效组分生物碱和苷抗血小板聚集机制。方法大鼠分别给予补阳还五汤原方、生物碱、苷和噻氯匹定，进行ADP诱导的血小板聚集实验。取聚集前、后的血小板提取cAMP、cGMP，采用放免法检测血小板cAMP、cGMP。结果各组血小板聚集比较，生物碱组、苷组和噻氯匹定组血小板聚集强度与空白组相比显著降低（P〈0．01）。原方组血小板聚集强度与空白组相比显著降低（P〈0．05）。血小板聚集后cAMP含量降低（P〈0．01）．而原方、生物碱、苷和噻氯匹定均可抑制ADP诱导的血小板cAMP下降（P〈0．05，P〈0．01）。血小板聚集后cGMP含量降低（P〈0．01），原方、生物碱、苷和噻氯匹定也可抑制聚集后血小板cGMP下降（P〈0．05，P〈0．01）。结论生物碱、苷、原方和噻氯匹定可抑制ADP诱导的大鼠血小板聚集，各药可抑制血小板聚集后血小板内cAMP、cGMP的下降，提示其抗血小板聚集作用是通过抑制聚集后血小板内环核苷酸降低而实现的。     

二磷腺苷受体拮抗药的抗血栓应用

二磷腺苷 (ＡＤＰ)是重要的血小板激动药[1] 。ＡＤＰ受体拮抗药能阻断血小板的激活反应 ,作用于凝血酶、胶原 ,从而抑制血小板聚集 ,发挥抗血栓作用。现将国内外已上市的两种ＡＤＰ受体拮抗药简要介绍如下。1　噻氯匹定 (ｔｉｃｌｏｐｉｄｉｎｅ)由法国Ｓａｎｏｆｉ公司开发上市 ,1997年ＦＤＡ批准在美国销售 ,国产噻氯匹定 1997年被批准投产 ,目前该药已在全世界 3 0多个国家批准上市。1.1　抗血小板聚集作用　在一项 14 9例血小板聚集功能≥5 0 %的患者参加的前瞻性研究中 ,试验组口服盐酸噻氯匹定2 5 0ｍｇ/ｄ ,对照组口服肠溶阿司匹林 …     

噻氯匹定对脑梗死病人血小板聚集的影响

目的：观察噻氯匹定对急性脑梗死的治疗效果及其对血小板聚集的影响。方法：脑梗死病人１１９例，随机分成噻氯匹定组和基础治疗（右旋糖酐＿４０，三磷腺苷二钠，辅酶Ａ，胞磷胆碱等）对照组，观察疗效，并于治疗前、治疗７ｄ和１６ｄ后检测血小板聚集率。结果：噻氯匹定组有效率达９６％；明显降低血小板聚集率，较对照组有显著性差异。结论：噻氯匹定可用于脑梗死急性期的治疗，抑制血小板聚集是其重要的治疗机制。     

氯吡格雷的抗栓作用

氯吡格雷 (clopidogrel)是一种新型的噻吩吡啶类衍生物 ,具有拮抗ADP诱导的血小板聚集和抗栓作用 ,其抗血小板聚集活性比噻氯匹定 (ticlopi dine)强数十倍 ,且比噻氯匹定有更好的耐受性和较小的副作用 ,与噻氯匹定一样 ,其原形并无活性 ,必须在体内代谢为有效活性产物时才有抗栓作用。这些已经在动物试验中证实 ,目前我国也正用于Ⅱ期临床试验。本文着重记述氯吡格雷的生化药理、作用原理及抗栓活性     

噻氯匹啶对血小板聚集功能的抑制作用研究

观察了噻氯匹啶(TP)对血小板聚集的影响,结果表明在体外可显著抑制ADP、花生四烯酸和凝血酶诱导的大鼠或人血小板聚集,其IC₅₀分别为1.035、1.047和0.092mmol/L,在体内连到给药(TP:50-200mg/kg·d^-1)7d可抑制ADP和凝血酶诱导的大鼠血小板聚单,提示TP是一个较强的血小板聚集抑制剂。     

噻氯匹定对2型糖尿病病人血小板活化状态的影响

目的 :观察噻氯匹定对 2型糖尿病病人血小板活化状态的影响。方法 :48例 2型糖尿病病人口服噻氯匹定 2 5 0mg ,每日 1次 ,疗程 4wk。结果 :治疗后 ,病人的血小板聚集率、血小板α颗粒膜蛋白、凝血烷B2 (TXB2 )的差值分别为 (-1 1±9) % ,(-5 4± 49) μg·L-1,(-71± 65 )ng·L-1均显著下降 (P <0 .0 1 ) ;6 酮 前列腺素F1α(6 K PGF1α)上升 ,差值为 (4± 4)ng·L-1,T/K(TXB2与 6 K PGF1α的比值 )比值下降 ,差值为 -5± 4,差异有非常显著意义 (P <0 .0 1 )。结论 :噻氯匹定能有效地降低 2型糖尿病病人的血小板聚集率、改善血小板活化状态、恢复体内T/K的平衡     

常用抗血小板制剂疗效及性别差异的比较

目的：观察噻氯匹定,阿斯斯匹林（ＡＳＡ）抑制血小板聚集功能在男女患者疗效的差异性。方法：１２４例用药前血小板聚集功能≥５０％者入选,男女患者各６２例,再随机分成噻氯匹定Ｔ组（男Ｔ１、女Ｔ２）和阿斯匹林Ｃ组（男Ｃ１、女Ｃ２）,Ｔ组口服噻氯匹定２５０ｍｇ／ｄ,Ｃ组口服ＡＳＡ ７５ ｍｇ／ｄ均为４周,服药后２周末、４周末测定血小板聚集功能（ＡＤＰ）诱导０．２μｍｏｌ／Ｌ）．结论：证实噻氯匹定抗血小板聚集率优于ＡＳＡ。噻氯匹定显效率男６８％、女６２．８ ％,总有效率为男９６．８％,女９５．７％。且证明男女疗效无明显差异．而ＡＳＡ显效率男１８％、女１３％,总有效率男７２．３％女１５％,男女疗效有显著不同。     

噻氯匹定抗血小板活性和长期服用的安全性

噻氯匹定(Ticlopidine)是一种新的血小板聚集抑制剂,经体外试验,它能抑制二磷酸腺苷、胶原、凝血酶、花生四烯酸和肾上腺素引起的血小板聚集作用,延长出血时间。其作用机制尚不清楚。作者研究评价了噻氯匹定对23例一过性局部缺血性脑血管疾患者的血小板功能的影响,以及长期服用本品可能引起的副作用。     

Effect of racemic ibuprofen dose on the magnitude and duration of platelet cyclo-oxygenase inhibition: relationship between inhibition of thromboxane production and the plasma unbound concentration of S(+)-ibuprofen.

1. Four healthy male subjects received racemic ibuprofen (200, 400, 800 and 1200 mg), orally, on four occasions, 2 weeks apart, according to a four-way Latin-square design, in order to investigate the influence of increasing dose of ibuprofen on the magnitude and duration of its antiplatelet effect as well as on the relationship between such effect and drug concentration. 2. The antiplatelet effect of ibuprofen was assessed by measuring the inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood. The plasma unbound concentration of S(+)-ibuprofen, the enantiomer shown in an in vitro study to be responsible for the inhibitory effect of platelet TXB2 generation, was measured using an enantioselective method. 3. The maximum percentage inhibition of TXB2 generation increased significantly with dose from a mean +/- s.d. of 93.4 +/- 1.2% after the 200 mg dose to 98.8 +/- 0.3% after the 1200 mg dose, and there was an increase with dose in the duration of inhibition of TXB2 generation. The effect of ibuprofen on platelet TXB2 generation was transient and mirrored the time-course of unbound S(+)-ibuprofen in plasma; on all but one of the 16 occasions, serum TXB2 concentrations returned to at least within 10% of the pretreatment concentrations within 24 h of ibuprofen administration. 4. For each subject, the relationship between the percentage inhibition of TXB2 generation and the unbound concentration of S(+)-ibuprofen in plasma was modelled according to a sigmoidal Emax equation. The mean plasma unbound concentration of S(+)-ibuprofen required to inhibit platelet TXB2 generation by 50% (EC50) was 9.8 +/- 1.0 micrograms l-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

去氢紫堇碱对兔血小板TXB2及主动脉6-keto-PGF1PGF1α含量的影响

Dehydrocorydaline (DHC) was shown to reduce the production of thromboxane B₂ (TXB₂)in platelets and 6-keto-prostaglandin F_1α (6-keto-PGF_1α in the aorta of rabbits in vitro. The effect of DHC increased with the increase of dose.DHC 0.41 mg was found to inhibit the formatiom of TXB₂ markedly while not reduce the content of 6-keto-FCF_1α. DHC also exhibited obvious inhibitory effect on the arachidonic acid (0.66mmol/L) induced formation of platelet malondialdehyde (MDA). These effects were similiar to the specific cycloxygenase inhibitor, aspirin (0.03 mg/ml). The results suggest that (1) DHC reduced both contents of TXA₂ and PGI₂ in vitro. (2) DHC markedly inhibited the system of cycloxygenase in cell microsomes. (3) As to whether TXA₂ synthetase or cycloxygenase was inhibited in these experiments is still to be elucidated.     

Effects of low-dose aspirin on responses to furosemide

We assessed the effects of low-dose aspirin (0.5 and 15 mg/kg/d) on renal prostaglandin synthesis and action in healthy volunteers using intravenous furosemide as a stimulus. Inhibition of platelet cyclo-oxygenase was assessed by changes in serum thromboxane B2 (TXB2) level. After one week of treatment, ten healthy subjects did not show any change in weight, blood pressure, or diuretic and natriuretic responses to furosemide with either dose of aspirin. Serum TXB2 level was reduced to 3% of control by aspirin 0.5 mg/kg/d and to 0.1% by the higher dose. In contrast, urine excretion of TXB2 was only reduced to 68% and 51% of the placebo value, whereas 6-keto-prostaglandin F1 alpha (6kPGF1 alpha) excretion was not decreased by either dose. Furosemide produced a transient increase in excretion rates of TXB2 and 6kPGF1 alpha that was of lesser duration than the diuretic response. These transient increases were slightly reduced by aspirin. Baseline plasma renin activity was not affected by either dose of aspirin. The brisk increment in plasma renin activity seen ten minutes after furosemide, as well as later values (30 and 240 min) were not changed by aspirin. We conclude that chronic low-dose aspirin can profoundly affect platelet PG production without affecting stimulated renal PGI2 production or plasma renin activity. There is a modest reduction in urine TXB2 excretion that is consistent with a primarily renal source of this metabolite.     

Effects of the new antiplatelet agent 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine on platelet aggregation and thrombosis in experimental animals.

Antiplatelet and antithrombotic effects of KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) were studied. KC-764 inhibited arachidonic acid (AA)- and collagen-induced platelet aggregation with IC50s of 1.0 x 10(-8)-2.8 x 10(-7) mol/l for humans, rabbits, guinea pigs and dogs, and IC50s of 3.9 x 10(-6)-3.7 x 10(-5) mol/l for mice and rats in vitro. KC-764 inhibited AA- and collagen-induced aggregation with ID50s of 0.04-0.09 mg/kg p.o. in rabbits and dogs, and ID50 of 13.0 mg/kg p.o. in rats. These antiaggregatory activities of KC-764 were stronger than those of acetyl-salicylic acid (ASA), indometacin, cilostazol and ticlopidine. KC-764 inhibited the production of thromboxane B2 (TXB2) in rabbit platelet microsomes, washed platelets and reconstituted platelet rich plasma (RPRP) with IC50s of 2.9 x 10(-6) mol/l, 2.8 x 10(-7) mol/l and 4.3 x 10(-8) mol/l, respectively. The in vitro inhibitory activity of KC-764 on AA-induced platelet aggregation was more potent when RPRP was used rather than washed platelet suspension containing 30% rabbit plasma. ASA did not show such an augmentation. KC-764 prevented collagen- and AA-induced thrombosis at more than 1 mg/kg p.o. and more than 0.1 mg/kg i.v. in mice and rabbits. KC-764 showed the wider margin of dose between antiplatelet action and prolongation of bleeding time in rabbits than ASA and indometacin. These results indicated that KC-764 was a potent antithrombotic drug to prevent TXB2 production and less possible to induce untoward actions as compared with ASA or indometacin.     

Effects of propranolol in vitro and in vivo on platelet function and thromboxane formation in normal volunteers

In vitro and ex vivo effects of propranolol on platelet aggregation, formation of thromboxane B2 (TXB2) and platelet sensitivity to prostacyclin were studied in healthy men. Propranolol, added in vitro to platelet rich plasma (PRP) inhibited platelet aggregation and TXB2 formation induced by ADP, 1-epinephrine, collagen and arachidonic acid. Concentrations of 20-100 microM propranolol were effective when ADP, 1-epinephrine and collagen were used as stimuli. Higher concentrations (250-500 microM) were needed to inhibit aggregation induced by arachidonic acid. Oral administration of propranolol either as a single dose (120 mg) or for one week (3 x 40 mg/day) did, however, not affect platelet aggregation, thromboxane formation and platelet sensitivity to prostacyclin. In addition, withdrawal of propranolol was without effect on these parameters. Although propranolol has potent effects on platelet function in vitro, it seems that the blood levels achievable by oral administration of propranolol are too low to affect platelet aggregation and TXB2 formation.     

Effects of ticlopidine on blood fibrinogen and blood viscosity in peripheral atherosclerotic disease

Ten patients with peripheral atherosclerotic disease(PAD) treated with 750 mg/d of 5-(2-chlorophenylmethyl)-4,5,6,7-tetrahydrothieno (3,5-c-pyridine) hydrochloride (ticlopidine, Tiklid) were studied for three months. As control was studied a similar group of patients treated with a traditional vasodilator (nicotinate). The aim of our study was to evaluate the effect of ticlopidine both on the clinical evolution of the disease and on rheologic, coagulative and platelet parameters. A progressive increase of maximal walking distance was noted during the three months of therapy with ticlopidine and limited to the first 30 days of treatment with nicotinate. The fibrinogen levels resulted significantly lowered during 90 days of treatment with ticlopidine, while that was not evident in the nicotinate group. There was also a slight improvement of blood viscosity in the ticlopidine group (not evident in the nicotinate group), but it was not statistically significant. No further modifications of investigated data were found in the two groups of patients. The clinical benefit of ticlopidine in PAD without adverse reactions can be confirmed at least at the dosage of 750 mg/d instead of the usual dose of 500 mg/d. A direct or indirect action of ticlopidine on plasma fibrinogen is suggested. This observation may supply new clues for the understanding of the mechanism of action of this drug.     

Effects of clopidogrel and ticlopidine on experimental diabetic ischemic retinopathy in rats

Ticlopidine, a thienopyridine that prevents the progression of diabetic retinopathy in humans, was recently shown to increase nitric oxide (NO) production in human neutrophils. The thienopyridine clopidogrel has been found to be clinically useful in the secondary prevention of thrombotic events. The aim of the present study was to evaluate the effect of clopidogrel on ischemic retinopathy in streptozotocin-diabetic rats and its influence on prostanoids and NO production. We compared nondiabetic rats and rats after 3 months of diabetes that were given three doses (1, 10 or 20 mg/kg per day p.o.) of ticlopidine or clopidogrel from the first day of diabetes.The variables recorded after 3 months of diabetes were platelet aggregation, thromboxane B(2) (TxB(2)) production, 6-keto-prostaglandin F(1)(alpha) (stable metabolite of prostacyclin), aortic NO, plasma nitrites/nitrates, and the percentage of the retinal surface occupied by horseradish peroxidase (HRP)-permeable vessels. In diabetic rats, platelet aggregation and thromboxane concentration were increased, and prostacyclin, NO and area occupied by HRP-permeable vessels were decreased.Ticlopidine and clopidogrel reduced the maximum extent of platelet aggregation in a dose-dependent manner: maximal inhibition with respect to untreated diabetic rats was 48.6% with ticlopidine and 66.6% with clopidogrel. Ticlopidine reduced thromboxane B(2) only at a dose of 20 mg/kg per day p.o. (47.4% inhibition) and clopidogrel at doses of 10 mg/kg per day (51% inhibition) or 20 mg/kg per day (51.7% inhibition). Aortic prostacyclin production did not change after treatment with either thienopyridine. Treatment with ticlopidine reduced the inhibition of NO production in untreated rats (89.6% inhibition) to 0.9%, and clopidogrel reduced inhibition to 30%. Treatment with ticlopidine or clopidogrel reduced the retinal nonperfused area from 86.8% inhibition in untreated rats to 45.6% and 25.3%, respectively.In conclusion, the early administration of thienopyridines in streptozotocin-diabetic rats partly prevented the appearance of diabetic retinal ischemia.     

Single oral dose study of two isosorbide-based aspirin prodrugs in the dog

The objective of this study was to compare two aspirin prodrugs, isosorbide diaspirinate (ISDA) and a nitroaspirin (ISMNA), with aspirin in terms of effects on dog platelet function after administration of a single oral dose. Groups of six dogs were administered ISDA (2mg kg(-1)), ISMNA (4 mg kg(-1)) or aspirin (2mg kg(-1)). Blood was sampled at 1, 2, 4, 8, 12 and 24 h post-dosing and evaluated for capacity to generate post-clotting thromboxane (TX)B2. The aggregation response to arachidonic acid (AA) (100 microM), ADP (30 microM) or collagen (10 microg mL(-1)) was estimated at each time-point using the whole blood impedance method. Plasma ISMN following oral administration of ISMNA was also measured and compared with plasma ISMN following administration of a physical mixture of ISMN and aspirin. ISDA administration (2 mg kg(-1)) was associated with a significant reduction (P < 0.05) in serum TXB2 at 12 and 24 h (>90%) post-dosing and persistent inhibition of AA-induced platelet aggregation. ISDA administration caused a more marked depression of post-clotting TXB2 levels than aspirin in this study, although its ability to inhibit platelet aggregation was less consistent than that of aspirin. The nitroaspirin ISMNA was least effective at inhibiting platelet aggregation response or TXB2 production. The ISMN AUC(0-24 h) for the ISMNA-treated dogs was 77% of that for the physical mix-treated dogs and the tmax was delayed. This study indicates that the two aspirin esters cause aspirin-like effects on platelet function, probably through aspirin release, when administered orally to dogs.     

Bioequivalence of two preparations of ticlopidine evaluated using a pharmacodynamic end point

OBJECTIVE: To evaluate the bio-equivalence of 2 ticlopidine preparations, 250 mg Iclopid tablets (Pabianickie Zaklady Farmaceutyczne, Polfa, Poland; test formulation) and 250 mg Ticlid tablets (Sanofi, France; reference formulation) using a pharmacodynamic end point, i.e the platelet aggregation test ex vivo. SUBJECTS, MATERIALS AND METHODS: The study was open, randomized, multiple-dose, two-period, crossover with a four-week washout interval. Volunteers were screened for sensitivity towards the platelet aggregation (ex vivo) effect of ADP (30 micromol/l) and sensitivity to the antiplatelet activity of ticlopidine (250 mg daily, for 3 consecutive days). Only those responding to 30 micromol/l of ADP with aggregation in the range of 40 - 75% of control (0.9% NaCI), and those responding to ticlopidine within 40 - 75% of inhibition of platelet aggregation to ADP ex vivo were randomized to the study. The dose of ticlopidine in each phase was 250 mg daily for four days. Blood samples were taken on Day 0 and Days 2, 4 (last day of ticlopidine administration), 5, 6, 9, 11 and 16 in order to follow platelet recovery. The pharmacodynamic parameter measured was expressed as the percentage inhibition of ex vivo platelet aggregation calculated from the number of platelets in the sample of whole blood remaining after ADP (30 micromol/l) compared to the control sample. The following values were calculated: area under the inhibition curve of platelet aggregation (AUC(inh 1-16)), maximal inhibition of platelet aggregation (Max(inh)) and time at which maximal inhibition of aggregation occurred (T(max inh)). RESULTS: The ratios (90% confidence intervals) of Iclopid/Ticlid for AUC(inh 1-16), Max(inh), and T(max inh) were: 1.008 (0.973 - 1.044), 1.009 (0.991 - 1.028) and 1.015 (0.988 - 1.043), respectively, satisfying the bioequivalence criteria. CONCLUSIONS: The test and the reference products are bioequivalent on the basis of the ex vivo platelet aggregation test. Our study has shown that the bioequivalence of two different preparations can be assessed by measuring a pharmacodynamic end point in a suitably selected group of subjects.     

三乙酰莽草酸对血小板聚集的抑制作用

目的：研究三乙酰莽草酸（TSA）对血小板聚集功能的抑制作用及其作用机理。方法：用比浊法测定血小板聚集功能,分光光度法测定MDA的含量,放免法测定TXB₂,6-酮-PGF_1α,cAMP和cGMP的含量。结果：TSA 12.5,25,50,100和200 mg.kg^-1 ig明显抑制ADP和胶原诱导的大鼠血小板聚集;TSA 12.5,50和200　mg.kg^-1 ig显著增加大鼠血小板内cAMP水平,但不影响cGMP水平。TSA 200 mg.kg^-1对AA诱导的血小板中MDA的生成,ADP诱导的血小板中TXB2和腹主动脉壁6-酮-PGF_1α的生成有轻度抑制作用。结论：TSA抑制血小板聚集作用部分与血小板内cAMP水平升高有关。