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- The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease. [JOURNAL ARTICLE]
- Thromb Haemost 2014 Jul 10; 112(3)
CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC[0-tlast]), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC(0-tlast) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [CI]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VN-PRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p≥0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.
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- Anasthesiol Intensivmed Notfallmed Schmerzther 2014 Jun; 49(6):388-395.
Management of ischemic stroke is targeted on four therapeutic objectives: limitation of neurological deficit, prevention of earyl stroke recurrence, protection against complications, and secondary prevention. Intravenous thrombolysis within 4.5h of stroke onset is the only proven therapy to improvefunctional outcome. Although promising, neither endovascular recanalisation nor neuroprotective strategies have demonstrated efficacy so far. Immediate administration of antiplatelet agents like acetylsalicylic acid and clopidogrel - in case of intravenous thrombolysis at the earliest after 24h - is effective to prevent early stroke recurrence, whereas anticoagulants should be ommitted in this stage because of an increased risk of cerebral hemorrhage. Subcutaneous heparin/low molecular weight heparin, mobilisation, nasogastric tube, and decompressive craniectomy may protect from venous thromboembolism, aspiration pneumonia, and malignant brain edema, respectively. Secondary prevention is guided by stroke etiology, e.g. oral anticoagulation in the presence atrial fibrillation or endarterectomy in case of sympomatic high-grade carotid stenosis.
- No misrepresentation of vital status follow-up in PLATO: Predefined analyses guarantee the integrity of the benefits of ticagrelor over clopidogrel in the PLATO trial: Commentary on: DiNicolantonio JJ, Tomek A, Misrepresentation of vital status follow-up: Challenging the integrity of the PLATO trial and the claimed mortality benefit of ticagrelor versus clopidogrel, International Journal of Cardiology, 2013 Serebruany VL. Discrepancies in the primary PLATO trial publication and the FDA reviews, International Journal of Cardiology, 2014. [LETTER]
- Int J Cardiol 2014 Jun 27.
- Functional characterization of 21 CYP2C19 allelic variants for clopidogrel 2-oxidation. [JOURNAL ARTICLE]
- Pharmacogenomics J 2014 Jul 8.
Genetic variations in cytochrome P450 2C19 (CYP2C19) contribute to interindividual variability in the metabolism of therapeutic agents such as clopidogrel. Polymorphisms in CYP2C19 are associated with large interindividual variations in the therapeutic efficacy of clopidogrel. This study evaluated the in vitro oxidation of clopidogrel by 21 CYP2C19 variants harboring amino acid substitutions. These CYP2C19 variants were heterologously expressed in COS-7 cells, and the kinetic parameters of clopidogrel 2-oxidation were estimated. Among the 21 CYP2C19 variants, 12 (that is, CYP2C19.5A, CYP2C19.5B, CYP2C19.6, CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.14, CYP2C19.16, CYP2C19.19, CYP2C19.22, CYP2C19.24 and CYP2C19.25) showed no or markedly low activity compared with the wild-type protein CYP2C19.1B. This comprehensive in vitro assessment provided insights into the specific metabolic activities of CYP2C19 proteins encoded by variant alleles, and this may to be valuable when interpreting the results of in vivo studies.The Pharmacogenomics Journal advance online publication, 8 July 2014; doi:10.1038/tpj.2014.30.
- Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction. [JOURNAL ARTICLE]
- Pharmacogenomics J 2014 Jul 8.
We examined clinical outcomes with proton pump inhibitors (PPI) use within CYP2C19 genotype groups during clopidogrel treatment following acute myocardial infarction (AMI). 2062 patients were genotyped for CYP2C19*2 and *17 variants in TRIUMPH. 12 month clinical outcomes were analyzed among patients discharged on clopidogrel within CYP2C19*2 carrier, CYP2C19*17 carrier, and CYP2C19*1 homozygote genotype groups. PPI use was not associated with a difference in mortality. Among clopidogrel-treated Caucasians following AMI, PPI use was associated with a significantly higher rate of cardiac rehospitalization (HR 1.62, 95% CI 1.19-2.19; P=0.002) compared with no PPI use. PPI users who were carriers of the CYP2C19*17 variant experienced significantly higher rates of cardiac rehospitalization (HR 2.05, 95% CI 1.26-3.33; P=0.003), carriers of the CYP2C19*2 variant had a trend toward increased 1-year cardiac rehospitalization (HR 1.69, 95% CI 0.95-2.99; P=0.07), while no significant differences were observed among CYP2C19*1 homozygotes. These results indicate that the risks associated with PPI use among clopidogrel-treated Caucasian post-MI patients are impacted by CYP2C19 genotype, and suggest knowledge of genotype may be useful for personalizing PPI use among patients following AMI to reduce rehospitalization.The Pharmacogenomics Journal advance online publication, 8 July 2014; doi:10.1038/tpj.2014.28.
- [Association between clopidogrel resistance and polymorphism of platelet adenosine diphosphate receptor in patients with coronary atherosclerotic disease]. [English Abstract, Journal Article]
- Zhejiang Da Xue Xue Bao Yi Xue Ban 2014 May 25; 43(3):333-8.
OBJECTIVE： To investigate the relation of clopidogrel resistance to polymorphism of adenosine diphosphate receptor (P2Y12).
METHODS： Three hundred and seventy patients with coronary atherosclerotic heart disease, who were admitted in hospital from May 2011 to November 2012 and underwent percutaneous coronary intervention, were enrolled in the study. All patients recieved antiplatelet therapy (oral aspirin 100 mg per night and clopidogrel 75 mg per day for >7 d). The gene polymorphisms of C34T and G52T P2Y12 receptor were detected by using DNA sequencing technique. The relationship of gene polymorphism with the incidence of clopidogrel resistance and clinical outcomes were analyzed.
RESULTS： Among 370 patients, clopidogrel resistance developed in 100 cases, including 36 males (36%) and 64 females (64%). In the C34T locus, 212 cases were of CC genotype and 158 were of CT+TT genotype; the incidence of clopidogrel resistance in CC genotype was significantly lower than that in CT+TT genotype (P<0.05). In the G52T locus, 218 cases were of GG genotype and 152 cases were of GT+TT genotype; the incidence of clopidogrel resistance in GT+TT genotype were significantly higher than that in GG genotype (P<0.05). After 1-year follow-up, patients with CC genotype had lower incidence of angina recurrence than patients with CT+TT genetype did (13.2% vs 19.6%, Χ2=4.956, P<0.05), and patients with GG genotype had lower incidence of emergency revascularization, angina, and cardiovascular composite endpoint events than patients with GT+TT genotype did (Χ2=4.135,6.823,5.916, Ps<0.05). CONCLUTION： T-34, -52 mutations on P2Y12 receptor gene may be a risk factor for clopidogrel resistance and adverse cardiovascular events.
- Gene polymorphism of cytochrome P450 2C19*2 and clopidogrel resistance reflected by platelet function assays: a meta-analysis. [JOURNAL ARTICLE]
- Eur J Clin Pharmacol 2014 Jul 5.
The relationship between CYP2C19*2 gene polymorphism and clopidogrel resistance reflected by platelet function assays has been studied extensively in the past several years, while no clear conclusion can be drawn from the previous studies. To explore a more precise estimation of the relationship, a meta-analysis was conducted in the present study.The relevant studies were identified by searching PubMed, EMBASE, the Web of Science, Cochrane Collaboration Database, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, and China Biological Medicine (CBM) up to February, 2014. The meta-analysis was performed by the STATA 11.Eight studies with a total of 2,331 subjects, including 1,066 patients with clopidogrel resistance and 1,265 patients without clopidogrel resistance were included. The pooled analysis showed that CYP2C19*2 gene polymorphism was probably associated with clopidogrel resistance (OR (95 % CI): GA vs. GG: 2.10 (1.74-2.53); AA vs. GG: 3.05 (2.10-4.45); dominant model: 2.22 (1.85-2.65); recessive model: 2.33 (1.62-3.36)). No statistically significant difference was found in the analysis of the three subgroups. The statistical stability and reliability was also demonstrated by the sensitivity analysis and publication bias outcomes.The meta-analysis suggests that CYP2C19*2 gene polymorphism may be associated with clopidogrel resistance.
- Monitoring the Efficacy of ADP Inhibitor Treatment in Patients With Acute STEMI Post-PCI by VASP-P Flow Cytometry Assay. [JOURNAL ARTICLE]
- Clin Appl Thromb Hemost 2014 Jul 2.
Dual antiplatelet treatment (DAPT) with clopidogrel and aspirin represents common approach in prevention of thromboembolic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). The drawback of clopidogrel treatment is large interindividual variability in response.Our article aims to suggesting the most convenient method in monitoring the DAPT of post-PCI patients.We analyzed the on-treatment platelet reactivity by light transmission aggregometry and vasodilator-stimulated phosphoprotein (VASP) flow cytometric assay. Samples were obtained in 3 intervals: first prior to PCI, then 1, and 30 days after PCI.Based on VASP-platelet reactivity index (PRI), we observed 100% response rate in prasugrel-treated patients and 62% to 73 % in the clopidogrel group. Overall, only 2 (7%) patients with the VASP-PRI value in therapeutic range had major adverse cardiovascular events.Our results hint VASP-phosphorylation assay as a relevant method for guiding and tailoring DAPT.
- The pharmacogenetics of carboxylesterases: CES1 and CES2 genetic variants and their clinical effect. [JOURNAL ARTICLE]
- Drug Metabol Drug Interact 2014 Jul 2.
Abstract Human carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are serine esterases responsible for the hydrolysis of ester and amide bonds present in a number of pharmaceutical products. Several common genetic variants of the CES1 and CES2 genes have been shown to influence drug metabolism and clinical outcomes. Polymorphisms of the CES1 gene have been reported to affect the metabolism of dabigatran etexilate, methylphenidate, oseltamivir, imidapril, and clopidogrel, whereas variants of the CES2 gene have been found to affect aspirin and irinotecan. Although the findings of these studies may be preliminary, they demonstrate the potential clinical utility of CES polymorphisms; however, more research is required, especially with respect to CES2. In this review, we outline the functional, molecular, and genetic properties of CES1 and CES2, and highlight recent studies that have shown relations between CES1 and CES2 variants and contemporary pharmacotherapy.
- [Dual platelet inhibitors in intensive care units.] [JOURNAL ARTICLE]
- Med Klin Intensivmed Notfmed 2014 Jul 3.
The introduction of clopidogrel was a milestone in the development of modern antiplatelet therapy. However, the shortcomings in the pharmacokinetics of clopidogrel have led to the development of alternative substances.The two new drugs prasugrel and ticagrelor were included in the current guidelines for the treatment of patients with acute coronary syndrome. These potent platelet inhibitors, however, are associated with an increased rate of bleeding events, which is of particular importance in critically ill patients. However, the new platelet inhibitors are less effective in patients with cardiogenic shock or patients treated with therapeutic hypothermia.Recent studies underscore the assessment of the net clinical benefit in patient management. Since there is only a thin line between efficacy and safety in critically ill patients, future studies for risk stratification of antiplatelet therapy in terms of personalized medicine are mandatory.