P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphate-induced platelet aggregation after initiation of clopidogrel therapy with a high loading dose.

A large variability in the antiplatelet response to clopidogrel has been consistently reported. Recently, a P2Y12 haplotype was shown to be associated with enhanced adenosine diphosphate (ADP)-induced platelet aggregation in healthy volunteers. The aim of this study was to test in patients (n = 416) scheduled for coronary artery stenting whether P2Y12 haplotype H2 carriage is associated with increased ADP-induced platelet aggregation after administration of a 600 mg loading dose of clopidogrel. Blood was drawn from the arterial sheath at least 2 h after administration of 100 mg aspirin and 600 mg clopidogrel. ADP-induced platelet aggregation was assessed in platelet-rich plasma with light-transmission aggregometry. P2Y12 haplotypes (H1/H2) and P2Y12 C32T genotypes were determined with TaqMan assays. Haplotype combinations and genotypes were not associated with parameters of ADP-induced platelet aggregation after administration of a 600 mg loading dose of clopidogrel. Maximal ADP (5 mumol/l)-induced platelet aggregation was similar in patients carrying haplotype H2 and homozygous carriers of haplotype H1 (43.9 +/- 21.4 versus 43.2 +/- 21.1%, respectively; P = 0.77). Carriage of P2Y12 H2 haplotype does not seem to affect the platelet response to a 600 mg loading dose of clopidogrel in coronary artery disease patients prior to stenting.     

AT1-receptor blockade with irbesartan improves peripheral but not coronary endothelial dysfunction in patients with stable coronary artery disease

Activation of the renin-angiotensin-aldosterone system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis. Studies evaluating the effect of AT1-receptor blockers on endothelial dysfunction in patients with coronary artery disease (CAD) revealed mixed results. Studies addressing the effects of AT1-receptor blockers on the coronary and peripheral function in the same study population, are still lacking. We therefore aimed to test the effects of long-term therapy with the AT1-receptor blocker irbesartan (IRB) on both, the coronary and peripheral endothelial function in patients with CAD. Seventy-two patients with CAD were randomly assigned to double-blinded treatment for 6 months with IRB 300 mg per day or placebo, respectively. Coronary and peripheral endothelial function were measured by intracoronary infusion of acetylcholine (final intracoronary concentration 10(-7.3) to 10(-5.6)M) and by determining flow-dependent dilation (FMD) of the brachial artery, respectively. IRB significantly improved FMD, while no change of coronary endothelial function was observed. Interestingly, plasma levels of N(G),N(G)-dimethyl-arginine, and the isoprostane excretion rate were not modified. IRB treatment improves peripheral but not coronary endothelial dysfunction in patients with CAD. Since reduced FMD of the brachial artery has been shown to be associated with a high-cardiovascular event rate, improvement of FMD by IRB may lead to better prognosis of patients with CAD.     

High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability.

AIM: To assess platelet inhibitory effects, interindividual variability in platelet inhibition as well as response to a 600 mg, compared to a standard 300 mg, clopidogrel loading dose (LD) after coronary stenting METHODS AND RESULTS: Platelet function profiles were assessed in 50 patients undergoing coronary stenting receiving either a 300 mg (n=27) or 600 mg clopidogrel LD. ADP (6 microM) and collagen (6 microg/mL) induced platelet aggregation, as well as ADP (2 microM) induced glycoprotein (GP) IIb/IIIa activation and P-selectin expression were assessed at baseline and 4, 24, and 48 h following clopidogrel front-loading. A more intense and rapid inhibition of platelet activation (both GP IIb/IIIa activation and P-selectin expression) were achieved using a 600 mg, compared to a 300 mg, LD throughout the entire 48 hours (p<0.001). Although there were no differences in platelet aggregation, overall a 600 mg LD increased the number of clopidogrel responders and this was also achieved earlier compared to a 300 mg LD. A 600 mg LD did not reduce interindividual variability of platelet response. CONCLUSION: The use of a 600 mg clopidogrel LD in patients undergoing coronary stenting optimises platelet inhibitory effects early after intervention and may provide a more effective protection against early thrombotic complications.     

Arterial elasticity identified by pulse wave analysis and its relation to endothelial function in patients with coronary artery disease

Patients with coronary artery disease (CAD) have impaired endothelial function. Arterial elasticity is modulated by endothelial function. The association between arterial elasticity and endothelial function has not been reported in patients with CAD. The present study was designed to investigate whether endothelial dysfunction contributes to impaired arterial elasticity. Thirty patients with CAD and 30 control subjects were recruited. Large and small artery elasticity indices were non-invasively assessed using pulse wave analysis. Brachial artery endothelium-dependent and -independent function were assessed by vascular response to flow-mediated vasodilation (FMD) and sublingual nitroglyceride (NTG), respectively. C1 large artery elasticity index was not different in the CAD group compared with the control group. However, C2 small artery elasticity index was significantly reduced in the CAD group compared with the control group. Flow-mediated vasodilation (FMD) was also impaired in the CAD group compared with the control group. Flow-mediated vasodilation (FMD) in the brachial artery correlated with C2 small arterial elasticity index. But NTG-mediated brachial artery vasodilation was similar between the two groups. The present findings suggest that the patients with CAD have reduced C2 small arterial elasticity index and impaired FMD. Endothelial dysfunction is involved in diminished arterial elasticity, suggesting that C2 small arterial elasticity index is a novel surrogate measure for the clinical evaluation of endothelial function.     

不同负荷剂量氯吡格雷对血小板聚集率的影响

目的比较两种剂量氯吡格雷的起效时间及安全性,为急性冠状动脉（冠脉）综合征患者用药方案提供依据。方法60例急性冠脉综合征使用不同负荷剂量氯吡格雷患者随机分为A组（300mg）和B组（600mg）,均予氯吡格雷75mg／d后续治疗。以腺苷二磷酸（ADP）5μmol／L及20μmol／L作为诱导剂检测服药前及服药后2h和6h的血小板聚集率,并检测服药前及服药后第3天的血自细胞及血小板计数。结果在ADP20μmoL／L诱导的血小板聚集检测中,两组均显示服药后6h比服药后2h达到更高的血小板聚集抑制水平[A组（29．75±12．11）％比（43．63±14．31）％,P〈0．05;B组（28．86±10．24）％比（34．86±10．84）％,P〈0．05]。B组与A组相比,在服药后2h即起到更加明显的血小板聚集抑制作用[（34．86±10．84）％比（43．63±14．31）％,P〈0．05]。服药后3d内所有人选患者均无出血、自细胞减少及血小板减少等事件发生。结论氯吡格雷600mg作为负荷剂量较之300mg可以更快地达到较高水平的血小板抑制作用,且两者安全性相似。     

Effect of 150-mg vs 300-mg loading doses of clopidogrel on platelet function in Japanese patients undergoing coronary stent placement

BACKGROUND: The loading dose of ticlopidine is 500 mg in both the US and Europe and 200 mg in Japan. A lower loading dose of clopidogrel might achieve adequate platelet inhibition in Japanese patients. METHODS AND RESULTS: Platelet aggregation was serially measured at baseline, and 2, 4, 6, and 8 h after 150-mg (n=20) and 300-mg (n=20) clopidogrel loading. Platelets were stimulated with 5 and 20 micromol/L adenosine diphosphate (ADP) and aggregation was assessed by optical aggregometry. Pretreatment ADP-induced platelet aggregation in the 150-mg clopidogrel group did not differ from that of the 300-mg group. The administration of 300-mg clopidogrel loading dose resulted in lower platelet aggregation 2 h after the administration (5 micromol/L ADP: 53+/-9% vs 61+/-12%, p<0.05 and 20 micromol/L ADP: 61+/-10% vs 68+/-9%, p<0.05). A lower platelet aggregation induced with 20 micromol/L ADP was still observed 4 h after the 300-mg clopidogrel loading (58+/-10% vs 65+/-9%, p<0.05). CONCLUSIONS: The 150-mg clopidogrel loading does not achieve rapid platelet inhibition. The 300-mg loading dose should be used to suppress platelet function rapidly even in Japanese patients undergoing coronary stent placement.     

Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: results of the randomized, double-blind, placebo-controlled INEF study

High-density-lipoproteins-cholesterol (HDL-C) is invertedly related to the incidence of cardiovascular events. Recent studies suggest that HDL-C directly improves endothelial function. Nicotinic acid (niacin) effectively raises serum HDL-C. We therefore hypothesized that treatment with niacin improves endothelial dysfunction in patients with coronary artery disease (CAD). One hundred seven patients with CAD were randomly assigned to double-blinded treatment for 12 weeks with extended-release (ER)-niacin 1000 mg/day (N) or placebo (C), respectively. Flow-mediated dilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent dilation (NMD) and serum lipid concentrations were measured before and after treatment. Triglycerides (P=0.013), low-density-lipoprotein-cholesterol (LDL-C) (P=0.013) and HDL-C (P<0.0001) were altered by N compared to C. Niacin treatment was without effect on FMD or NMD, respectively, compared to placebo. However, post-hoc subgroup analysis revealed an improvement in FMD in patients with low HDL-C at baseline (absolute change in FMD (mean+/-S.D.) N: +3.25+/-3.88%, C: +1.03+/-2.71% in low tertile HDL-C 相似文献   

Evidence of platelet sensitization to ADP following discontinuation of clopidogrel therapy in patients with stable coronary artery disease

Epidemiological studies have linked clopidogrel discontinuation with an increased incidence of ischemic events. This has led to the hypothesis that clopidogrel discontinuation may result in a pharmacological rebound. We evaluated the impact of clopidogrel discontinuation on platelet function. Platelet aggregation was measured by light transmission aggregometry (LTA) in response to adenosine diphosphate (ADP) 0.5, 1, 1.5, 2.5, 5 and 10?µM and by VerifyNow® P2Y₁₂, in 37 clinically stable coronary artery disease (CAD) patients scheduled to discontinue clopidogrel treatment, and 37 clinically stable CAD patients not taking clopidogrel. Platelet function was assessed the day before clopidogrel cessation and 1, 3, 7, 14, 21 and 28 days after. Clopidogrel had been initiated a median of 555 days (ranging from 200 to 2280 days) before the treating cardiologist recommended its discontinuation. All participants were taking aspirin, most commonly 80?mg daily although a minority was prescribed 325?mg daily. Following clopidogrel discontinuation, VerifyNow® P2Y₁₂ did not detect any rebound platelet activity, but ADP-induced LTA showed platelet sensitization to ADP, particularly at low ADP levels. Increased platelet activity was detectable seven days after clopidogrel cessation and remained higher than in controls 28 days after discontinuation. No clinical event occurred in any of the participants during the 28 days following clopidogrel cessation. In conclusion, platelet sensitization to ADP as a consequence of chronic clopidogrel administration may partially explain the recrudescence of ischemic events following clopidogrel discontinuation in otherwise stable coronary artery patients.     

Effects of different doses of ticagrelor on platelet aggregation and endothelial function in diabetic patients with stable coronary artery disease

We performed this study to observe the effects of different doses of ticagrelor and standard-dose clopidogrel on platelet reactivity and endothelial function in diabetic patients with stable coronary artery disease (CAD). Sixty type 2 diabetic patients were assigned to one-quarter standard-dose ticagrelor, half standard-dose ticagrelor, standard-dose ticagrelor and standard-dose clopidogrel groups. Light transmission aggregometry (LTA) and VerifyNow assay were used to measure platelet function. Endothelial function was assessed by measurement of flow-mediated vasodilation (FMD) and plasma von Willebrand factor (VWF) levels were detected. Enzyme-linked immunosorbent assay (ELISA) examined the Interleukin-8(IL-8) and IL-10. The results suggested that the one-quarter dose (34.0%± 14.7%), half-dose (26.9%± 11.6%) and standard-dose (17.3%± 10.3%) ticagrelor showed lower platelet aggregation rate than clopidogrel (52.8%± 18.3%; P ＜0.0001). PRU values in three ticagrelor groups were lower than that in clopidogrel group (102 (76–184);75 (33–88);38 (11–52) versus 194 (138–271) and;P ＜0.0001). FMD levels were higher in ticagrelor groups compared with baseline levels while lower in clopidogrel group after treatment. However, no significant differences were found in the percentage increase in the FMD between ticagrelor groups and clopidogrel group. The levels of VWF after treatment were lower than the baseline levels, but there was no statistically significant difference between ticagrelor group and clopidogrel group after treatment. The concentration of IL-8 and IL-10 were decreased in patients with half and standard-dose ticagrelor group. In conclusion, one-quarter standard-dose ticagrelor produced similar inhibitory effects on platelet aggregation as standard-dose clopidogrel in diabetic patients with stable CAD. The half standard-dose ticagrelor had a similar inhibitory effect on platelet inhibition as standard-dose ticagrelor, which was stronger than that of clopidogrel. Moreover, the half-dose ticagrelor had equal protection of endothelial function and inhibition of inflammatory factor as standard-dose ticagrelor.     

Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease

We compared the antiplatelet effects of clopidogrel and the intravenous platelet P2Y 12 receptor antagonist AR-C69931MX, which acts on the same receptor as clopidogrel by a different and reversible mechanism and, unlike clopidogrel, is active in vitro . Thirteen patients with acute coronary syndromes entered into a phase II study of intravenous AR-C69931MX (Group 1) and eight patients undergoing intracoronary stent implantation and treated with clopidogrel (Group 2) were studied using a whole blood single-platelet counting aggregation assay. Group 2 patients were also studied using turbidimetry with ADP and TRAP as agonists and whole blood [ 14 C]5HT release to study dense granule secretion in response to ADP, collagen and TRAP. In Group 2 studies, a therapeutic concentration of AR-C69931MX was added in vitro before and after clopidogrel administration. AR-C69931MX in Group 1 achieved greater inhibition of ADP-induced platelet aggregation than clopidogrel in Group 2 and AR-C69931MX in vitro added to the effects of clopidogrel on ADP-induced aggregation. AR-C69931MX but not clopidogrel inhibited TRAP-induced aggregation and granule secretion and AR-C69931MX had a more consistent inhibitory effect on collagen-induced responses. In conclusion, therapeutic administration of clopidogrel moderately inhibits platelet P2Y 12 receptor activation and substantially greater P2Y 12 receptor blockade can be achieved with AR-C69931MX.     

Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome

OBJECTIVES: We sought to characterize the effects of clopidogrel on the activation of circulating platelets, the activation and aggregation of ex vivo platelets, and the interactions with leukocytes in patients with a non-ST-segment elevation in acute coronary syndromes (ACS). BACKGROUND: The significant benefits of clopidogrel in cardiovascular trials suggest that blockage of the P2Y(12) receptor may be associated with important biologic consequences. METHODS: Blood samples obtained from 23 ACS patients before and 24 h after a loading dose of clopidogrel (300 mg) were analyzed by whole-blood flow cytometry, light transmission aggregometry in platelet-rich plasma, and plasma enzyme-linked immunoassays. A thrombin receptor agonist peptide (TRAP) and adenosine diphosphate (ADP) were used as agonists. Normal individuals pretreated with aspirin served as controls. RESULTS: Clopidogrel attenuated platelet aggregation to both ADP (10 micromol/l) and TRAP (10 micromol/l) by 22% and P-selectin expression by 16% and 25%, respectively. The drug decreased the excess platelet-monocyte and platelet-neutrophil conjugates found in the blood of ACS patients (p < 0.01) and prevented their formation ex vivo with agonist stimulation. Plasma levels of soluble CD40L were reduced by 27% (p < 0.001) and of soluble P-selectin by 15% (p < 0.001). CONCLUSIONS: Clopidogrel attenuates the agonist effects of ADP and TRAP on platelet secretion, aggregation, and formation of platelet-monocyte and platelet-neutrophil conjugates in patients with ACS. These effects may all contribute to the clinical benefits of the drug in these syndromes.     

Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease

We compared the antiplatelet effects of clopidogrel and the intravenous platelet P2Y(12) receptor antagonist AR-C69931MX, which acts on the same receptor as clopidogrel by a different and reversible mechanism and, unlike clopidogrel, is active in vitro. Thirteen patients with acute coronary syndromes entered into a phase II study of intravenous AR-C69931MX (Group 1) and eight patients undergoing intracoronary stent implantation and treated with clopidogrel (Group 2) were studied using a whole blood single-platelet counting aggregation assay. Group 2 patients were also studied using turbidimetry with ADP and TRAP as agonists and whole blood [(14)C]5HT release to study dense granule secretion in response to ADP, collagen and TRAP. In Group 2 studies, a therapeutic concentration of AR-C69931MX was added in vitro before and after clopidogrel administration. AR-C69931MX in Group 1 achieved greater inhibition of ADP-induced platelet aggregation than clopidogrel in Group 2 and AR-C69931MX in vitro added to the effects of clopidogrel on ADP-induced aggregation. AR-C69931MX but not clopidogrel inhibited TRAP-induced aggregation and granule secretion and AR-C69931MX had a more consistent inhibitory effect on collagen-induced responses. In conclusion, therapeutic administration of clopidogrel moderately inhibits platelet P2Y(12) receptor activation and substantially greater P2Y(12) receptor blockade can be achieved with AR-C69931MX.     

Residual platelet activation through protease-activated receptors (PAR)-1 and ‐4 in patients on P2Y12 inhibitors

Background

Dual antiplatelet therapy with aspirin and thienopyridines has improved outcomes of patients after coronary stent implantation. However, current knowledge suggests that thrombin generation is not affected by inhibition of the P2Y12 receptor, and therefore, platelet activation may still occur.

Methods

The response to agonists specific for protease-activated receptors (PAR)-1 and ‐4 was tested by multiple electrode impedance aggregometry in 82 patients on stable doses of clopidogrel or prasugrel, and in 55 healthy controls.

Results

Based on the consensus cut-off value for adenosine diphosphate (ADP) responsiveness, only one out of 19 patients on prasugrel, but 22 out of 63 patients on clopidogrel had high on-treatment residual platelet reactivity in response to exogenous ADP (p = 0.01). Among the patients with adequate ADP P2Y12 receptor inhibition (n = 59), we still observed 32 patients (54.2%) with normal response to the PAR-1 activator SFLLRN (26 patients on clopidogrel, 81.2%; 6 patients on prasugrel, 18.8%), and 37 patients (63.8%) with a normal response to the PAR-4 activator AYPGKF (29 patients on clopidogrel, 78.4%; 8 patients on prasugrel, 21.6%). The degree of PAR-agonists inducible platelet activation was directly correlated with the activation induced by ADP (r > 0.5 and p < 0.001 for both agonists). Moreover, SFLLRN and AYPGKF inducible platelet reactivities were strongly correlated (r = 0.75, p < 0.001).

Conclusion

PAR responsiveness is preserved in the majority of patients with adequate clopidogrel-mediated inhibition of the platelet P2Y12 receptor, and still in about 20% of those with adequate inhibition by prasugrel.     

Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease.

AIMS: P2Y(12) receptor antagonism and platelet inhibition by prasugrel vs. clopidogrel were investigated in patients with stable coronary artery disease. METHODS AND RESULTS: One hundred and ten aspirin treated subjects were randomized to double-blind treatment with clopidogrel (n = 55) 600 mg loading dose (LD) and 75 mg maintenance dose (MD) or prasugrel (n = 55) 60 mg LD and 10 mg MD for 28 days. Concentrations of prasugrel and clopidogrel active metabolites were determined. Platelet aggregation to 20 microM adenosine diphosphate, measured by light transmission aggregometry, was reported as maximal platelet aggregation (MPA). P2Y(12) function was assessed by the vasodilator-stimulated phosphoprotein assay and reported as platelet reactivity index (PRI). The same pharmacodynamic measurements were performed after ex vivo addition of clopidogrel's active metabolite. At 2 h post-LD, mean MPA was 31 vs. 55%, and mean PRI 8.3 vs. 55.9% for prasugrel and clopidogrel, respectively (P < 0.001). During MD on day 14 and 28, mean MPA was 42 vs. 54% and mean PRI was 25 vs. 51%, respectively (P < 0.001). Peak level of the active metabolite and P2Y(12) inhibition occurred earlier and was greater with prasugrel (P < 0.001). Mean area under the time-concentration curve (AUC; microM.h) of the respective active metabolite was higher with prasugrel vs. clopidogrel post-LD (1.11 vs. 0.24) and post-MD (0.16 vs. 0.062). Ex vivo addition of clopidogrel's active metabolite further reduced PRI in all patients whose platelets were not already maximally inhibited. CONCLUSION: In aspirin-treated subjects with coronary artery disease, prasugrel 60/10 mg provides faster onset and greater inhibition of P2Y(12) receptor-mediated platelet aggregation than clopidogrel 600/75 mg, because of greater and more efficient generation of the active metabolite.     

Inhibition of platelet aggregation by prostaglandin E1 (PGE1) in diabetic patients during therapy with clopidogrel and aspirin

Diabetes mellitus (DM) is associated with increased platelet activation and reduced platelet inhibition by clopidogrel. Prostaglandin E1 (PGE1) stimulates adenyl cyclase activity in platelets and increases cyclic AMP concentrations, which inhibit Ca²⁺release and platelet aggregation induced by P2Y1 receptor activation. PGE1 is included in the VerifyNow P2Y12 assay to suppress P2Y1 induced platelet aggregation. We hypothesized that diabetes mellitus may be associated with altered response to PGE1 in subjects treated with clopidogrel. Subjects with established coronary artery disease who were taking clopidogrel 75?mg daily and aspirin for >14 days were enrolled (n?=?96). Diabetic (n?=?34) were compared with non-diabetic subjects (n?=?62). VerifyNow P2Y12 assay and light transmittance aggregometry (LTA) were performed using ADP as agonist with and without addition of PGE1. Genomic DNA was genotyped for common cytochrome P450 (CYP) 2C19 variants using Taqman assays. Residual on-treatment platelet aggregation induced by 20?µM ADP was not significantly different between subjects with and without DM. Addition of 22?nM and 88?nM PGE1 to 20?µM ADP resulted in a significant reduction of maximal platelet aggregation (MPA). Residual LTA platelet aggregation with PGE1 and VerifyNow P2Y12 platelet reactivity were significantly higher in subjects with DM than those without DM and in carriers of CYP 2C19*2 polymorphism. We conclude that an impaired inhibitory response to PGE1 may contribute to the high platelet reactivity phenotype in subjects with DM treated with clopidogrel. Addition of PGE1 to ADP agonist platelet assays may identify subjects with blunted inhibitory response to prostaglandins and result in a higher proportion of subjects with DM being classified as non-responders.     

Antiplatelet effects of a 600 mg loading dose of clopidogrel are not attenuated in patients receiving atorvastatin or simvastatin for at least 4 weeks prior to coronary artery stenting.

AIMS: To test prospectively whether the antiplatelet effect of a 600 mg loading dose of clopidogrel is attenuated in patients receiving atorvastatin and simvastatin for at least 4 weeks prior to coronary artery stenting. METHODS AND RESULTS: Blood samples were obtained at least 2 h after receiving 100 mg aspirin and 600 mg clopidogrel and prior to coronary stenting from 90 patients without statin therapy and 90 patients with statin (atorvastatin and simvastatin) therapy for at least 4 weeks. Maximal and residual platelet aggregation was evaluated with optical aggregometry in response to ADP (5 and 20 micromol/l). Surface expression of IIb/IIIa (CD61) and P-selectin (CD62) was assessed with whole blood flow-cytometry at baseline and following stimulation (5 and 20 micromol/l ADP). Inhibition of ADP-induced platelet aggregation was not impaired in the presence of concomitant statin therapy. Moreover, patients with and without statin therapy did not differ in respect to all flow-cytometric parameters obtained. CONCLUSION: The antiplatelet effect of a high, 600 mg loading dose of clopidogrel is not diminished in patients receiving atorvastatin and simvastatin for at least 4 weeks prior to coronary stenting.     

Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention

This study assessed the effect of body mass index (BMI) on platelet aggregation after administration of a high loading dose of clopidogrel 600 mg. Blood samples of 402 patients before percutaneous coronary intervention were collected >or=2 hours after administration of clopidogrel 600 mg. Platelet aggregation was measured in response to adenosine diphosphate (ADP; 5 and 20 microM). Patients were categorized as normal weight (BMI <25 kg/m(2)) or overweight (BMI >or=25 kg/m(2)). ADP-induced platelet aggregation was significantly higher in overweight patients than in normal-weight patients (46.0 +/- 21.8% vs 38.2 +/- 19.3% for ADP 5 microM, p = 0.0007; 55.1 +/- 22.7% vs 45.2 +/- 21.7% for ADP 20 microM, p <0.0001). Multivariate analyses demonstrated high BMI as the only independent predictor for increased ADP-induced platelet aggregation (p 相似文献   

Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function--a flow cytometry study.

AIMS: Clopidogrel is a pro-drug which is converted to an active, unstable drug by cytochrome P450 (CYP). The active drug irreversibly blocks one specific platelet adenosine 5'-diphosphate (ADP) receptor (P2Y12). It has been recently suggested that the most abundant human CYP isoform, 3A4, activates clopidogrel. Since certain lipophilic statins (i.e. simvastatin, atorvastatin, lovastatin) are a substrate of CYP3A4, we were interested in potential drug interactions between clopidogrel and statins. METHODS: In patients with coronary artery disease (n=47) in whom clopidogrel treatment was initiated for balloon angioplasty and stent implantation, blood samples were taken at 0, 5 and 48 h after oral administration of clopidogrel (loading dose 300 mg, followed by 75 mg daily). ADP-stimulated (1, 10, 100 micromol/l) expression of P-selectin (CD62P) on platelets was measured by flow cytometry, and used as a marker for the antiplatelet effect of clopidogrel. RESULTS: Pre-treatment with statins (atorvastatin, simvastatin) reduced significantly (10 micromol/l ADP stimulation) the inhibitory effects of clopidogrel during the loading phase (relative reduction after 5 h 29.3%) and, to a lesser extent during the maintenance phase (relative reduction after 48 h 16.6%). In addition we found a considerable individual heterogeneity in the response and three patients (6%) were identified in whom clopidogrel exerted almost no effect. CONCLUSION:Certain statins which are substrates of the CYP3A4 isoform competitively inhibit the metabolic activation of clopidogrel. As a result the relative clopidogrel induced platelet inhibition (P-selectin-expression) is diminished--but still there is a relative clopidogrel effect of more than 80% in the maintenance phase. It may be reasonable to test the therapeutic efficacy of clopidogrel in those patients who require long-term treatment.     

Inhibitory effects of P2Y12 receptor antagonists on TRAP-induced platelet aggregation, procoagulant activity, microparticle formation and intracellular calcium responses in patients with acute coronary syndromes

Thrombin induces platelet aggregation and membrane rearrangements leading to enhanced procoagulant activity and microparticle production, all of which are thought to contribute to thrombus formation in patients with acute coronary syndromes (ACS). Clopidogrel, an adenosine diphosphate (ADP) receptor antagonist acting at the P2Y(12) receptor, has been shown to provide clinical benefit in ACS. We aimed to investigate the effects of clopidogrel ex vivo and another ADP-antagonist, AR-C69931MX in vitro on thrombin receptor activating peptide (TRAP)-induced platelet aggregation, procoagulant activity, microparticle formation and [Ca(2+)]i responses in patients with ACS. Measurements were performed in platelet-rich plasma using aggregometry and flow cytometry (n = 12). Clopidogrel (300 mg loading dose plus 75 mg daily) significantly inhibited TRAP-induced aggregation, procoagulant activity (annexin V binding) and microparticle production (all P < 0.05) but not as extensively as AR-C69931MX (400 nmol/l). [Ca(2+)]i responses induced by a combination of TRAP and ADP designed to mimic the physiological effects of released ADP showed that clopidogrel partially and AR-C69931MX completely removed the ADP component of the [Ca(2+)]i responses (n = 6). The results provide new information on the mechanisms involved in the beneficial effects of P2Y(12) antagonists in patients with ACS.     

Association of P2Y12 C34T、G52T polymorphism and clopidogrel resistence in coronary artery disease in North Chinese

Objectives To assess the possible association between P2Y12 C34T、G52T polymorphism and clopidogrel resistance in coronary artery disease(CAD) of North China. Methods A case-control study was conducted in 615 patients with angiographically documented CAD.All 615 patients was detected platelet aggregation ratio,and accorded the platelet aggregation ratio to defined Clopidogrel resistance (CR) and None-Clopidogrel resistance(NCR),5μmol/L ADP-induced platelet aggregation ratio≥70%was defined CR.The P2Y12 C34T、G52T single nucleotide polymorphism was selected and genotyped.Results The genotype frequencies of CC,CT and TT of P2Y12 C34T polymorphism were 38.36%,50.68%and 10.96%in clopidogrel resistance patients, 50.96%,43.07%and 5.97%in non-clopidogrel resistance patients(P=0.010).The frequencies of P2Y12 C34T T allele frequencies in CR and NCR were 36.30%and 27.51% (P=0.004).The genotype frequencies of GG,GT and TT of P2Y12 G52T polymorphism were 74.66%,24.66%and 0.68%in clopidogrel resistance patients,79.74%,19.83% and 0.43%in non-clopidogrel resistance patients(P>0.05). The frequencies of P2Y12 G52T T allele frequencies in CR and NCR were 13.01%and 10.34%(P>0.05).After adjustment for conventional risk factors,including gender,age, body mass index,smoking status,hypertension,diabetes mellitus and hypercholesterolemia,there was significant difference between P2Y12 C34T polymorphism and clopidogel resistance (P =0.007).Conclusions The results suggest that P2Y12 C34T polymorphism might associated with clopidogrel resistance in CAD population of North China.