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- Effects of Cytochrome P450 2C19 and Paraoxonase 1 Polymorphisms on Antiplatelet Response to Clopidogrel Therapy in Patients with Coronary Artery Disease. [JOURNAL ARTICLE]
- PLoS One 2014; 9(10):e110188.
Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75-325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65-5.26; p<0.001) and 11.26 (95%CI, 2.47-51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70-1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98×10-6). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.
- Research on intracranial atherosclerosis from the East and west: why are the results different? [Journal Article, Review]
- J Stroke 2014 Sep; 16(3):105-13.
Intracranial atherosclerosis (ICAS) is a major cause of stroke worldwide and is more common in Asians than Caucasians. The study results from the East and West are generally similar, but notable differences exist. For example, studies from the East have reported that ICAS is associated with young age, whereas ICAS seems to be associated with old age in the West. Studies from the East have strongly suggested that mild ICAS associated with branch occlusion is one of the main causes of single subcortical infarction, whereas this aspect has not been considered in stroke classification systems developed in the West. While clopidogrel is commonly used in patients with large artery disease in the West, cilostazol has been more extensively studied and commonly used in ICAS patients in the East. A randomized controlled study from the West reported negative results regarding the efficacy of stenting in ICAS patients due largely to a relatively high rate of periprocedural adverse events, whereas research papers from the East have reported a relatively lower rate of complications. Studies to narrow these East-West gaps should be performed, including risk factor studies using homogenous ethnic populations, studies investigating appropriate classification systems, drug trials in different ethnic populations, and rigorous high standard randomized controlled studies on the efficacy of stenting in Eastern populations.
- Clopidogrel: A multifaceted affair. [JOURNAL ARTICLE]
- J Clin Pharmacol 2014 Oct 18.
Clopidogrel has been the therapy of choice, combined with aspirin, against platelet aggregation in patients at risk of suffering a vascular thrombotic event. Not all patients respond equally to clopidogrel, an observation that has led to searching for a test that, in the clinical setting, could predict patients' "resistance" to therapy. The evidence reveals a complex pharmacokinetic profile for clopidogrel, with multiple players involved, including cytochromes, characteristics of the target tissue and accompanying clinical conditions. Despite FDA Black Box warnings recommending CYP2C19 genotyping before clopidogrel use, no robust evidence indicates that CYP2C19 function determines clinical response to the drug, either based on the presence of loss of function alleles or drug interactions with CYP2C19 inhibitors, like omeprazole. A tailored anti-aggregation treatment based on ex vivo platelet reactivity also seems unlikely due to the lack of robustness of most assays. The identification of clinical conditions that are at higher risk of new cardiovascular events, such as diabetes, obesity, coronary artery disease, or specifc stenting procedures seems to be a prudent approach to tailor anti-platelet therapy with more powerful drugs, accompanied by careful counseling to promote patient compliance.
- Relation between the Change in Mean Platelet Volume and Clopidogrel Resistance in Patients Undergoing Percutaneous Coronary Intervention. [JOURNAL ARTICLE]
- Curr Vasc Pharmacol 2014 Oct 17.
We aimed to determine the association between the change in mean platelet volume (MPV) over time and aspirin/ clopidogrel resistance in patients undergoing percutaneous coronary intervention (PCI). The MPV and platelet function were analysed in 302 patients who underwent PCI. MPV changes were associated with increased aspirin reaction units (ARU, r = 0.114; P = 0.047), increased P2Y12 reaction units (PRU, r = 0.193; P = 0.001), and decreased P2Y12% inhibition (PI%, r = - 0.273; P < 0.001). The group with increasing MPV values showed significantly higher PRU values and lower PI% compared with the group with decreasing MPV values (222.5 ± 73.9 vs. 195.6 ± 63.7 PRU, P = 0.001; 24.1 ± 21.0 vs. 32.8 ± 18.5 PI%, P < 0.001, respectively). The clopidogrel resistant group (≥235 PRU or ≤15% of PI%) showed a significantly higher positive change in MPV (ΔMPV) values than the clopidogrel responder group (0.53 ± 0.78 vs. 0.13 ± 0.69 fL, P < 0.001). When the ΔMPV cut-off level was set at 0.20 fL using the receiver operating characteristic curve, the sensitivity and specificity for differentiating between the clopidogrel resistant and responder groups were 72.6% and 59.3%, respectively. After adjusting for traditional risk factors, the odds ratio in the clopidogrel resistant group with ΔMPV ≥0.2 fL was 4.10 (95% confidence interval; 1.84-9.17). In conclusion, ΔMPV was associated with PRU and PI%; a positive ΔMPV was an independent predictive marker for clopidogrel resistance after PCI.
- Evaluation of 89 Compounds for Identification of Substrates for Cynomolgus Monkey Cytochrome P450 2C76, a New Bupropion/Nifedipine Oxidase. [JOURNAL ARTICLE]
- Drug Metab Dispos 2014 Oct 15.
Cynomolgus monkeys are widely used in preclinical studies during drug development because of their evolutionary closeness to humans, including cytochrome P450 (P450 or CYP). Most cynomolgus monkey P450s are almost identical (≥90%) to human P450s; however, CYP2C76 has low sequence identity (approximately 80%) to any human CYP2Cs. Although CYP2C76 has no ortholog in humans and is partly responsible for species difference in drug metabolism between cynomolgus monkeys and humans, a broad evaluation of potential substrates for CYP2C76 has not yet been conducted. In this study, a screening of 89 marketed compounds, including human CYP2C and non-CYP2C substrates or inhibitors, was conducted to find potential CYP2C76 substrates. Among the compounds screened, 19 chemicals were identified as substrates for CYP2C76, including substrates for human CYP1A2 (7-ethoxyresorufin), CYP2B6 (bupropion), CYP2D6 (dextromethorphan), and CYP3A4/5 (dextromethorphan and nifedipine), and inhibitors for CYP2B6 (sertraline, clopidogrel, and ticlopidine), CYP2C8 (quercetin), CYP2C19 (ticlopidine and nootkatone), and CYP3A4/5 (troleandomycin). CYP2C76 metabolized a wide variety of the compounds with diverse structures. Among them, bupropion and nifedipine showed high selectivity to CYP2C76. As for nifedipine, CYP2C76 formed methylhydroxylated nifedipine, which was not produced by monkey CYP2C9, CYP2C19, or CYP3A4, as identified by mass spectrometry and estimated by a molecular docking simulation. This unique oxidative metabolite formation of nifedipine could be one of the selective marker reactions of CYP2C76 among the major CYP2C and CYP3A tested. These results suggest that monkey CYP2C76 contributes to bupropion hydroxylation and formation of different nifedipine oxidative metabolite(s) due to its relatively large substrate cavity.
- Uric acid levels and the risk of Contrast Induced Nephropathy in patients undergoing coronary angiography or PCI. [JOURNAL ARTICLE]
- Nutr Metab Cardiovasc Dis 2014 Sep 19.
Contrast Induced Nephropathy (CIN) is a common complication of procedures that require the use of contrast media, and seems to be mediated by oxidative stress and reactive oxygen species generation. Hyperuricemia is characterized by inhibited nitric oxide system and enhanced synthesis of reactive oxygen species. However, few studies have so far investigated the association between hyperuricemia and CIN that is therefore the aim of the current study among patients undergoing coronary angiography or percutaneous intervention.We analyzed a total of 1950 patients with Creatinine clearance <90 ml/min) undergoing elective or urgent coronary angiography and/or angioplasty. Patients were divided according to tertiles of baseline uric acid (Group 1, ≤5.5 mg/dL n = 653; Group 2, 5.6-7.0 mg/dL, n = 654; Group 3, ≥7.0 mg/dL, n = 643). CIN was defined as an absolute ≥0.5 mg/dl or a relative ≥25% increase in the serum creatinine level at 24 or 48 h after the procedure. Patients with higher uric acid levels were older, previous smokers, with higher prevalence of hypertension and diabetes, but with lower family history of CAD. They had more often history of a previous CABG and baseline renal dysfunction. Patients of the third Tertile had also higher levels of white blood cells, higher triglycerides and lower HDL-cholesterol and higher percentage of dilated cardiomyopathy/valvular disease as indication for angiography and consequently a lower prevalence of PCI. Patients with higher SUA were more often on therapy with ACE inhibitors and diuretics, but less often with statins, nitrate, ASA and Clopidogrel at admission. The occurrence of CIN was observed in 251 patients (12.9%), and was significantly associated with uric acid levels (12.3% in Group 1, 10.4% in Group 2 and 16.0% in Group 3; p = 0.04). Similar results were observed when the analysis was performed according to each tertiles values in both male and female gender. The association between elevated uric acid (≥7 mg/dl) and CIN was confirmed by multivariate analysis after correction for baseline confounding (Adjusted OR [95%CI] = 1.42 [1.04-1.93], p = 0.026). Similar results were observed across major subgroups of high-risk patients, such as patients with diabetes, female gender, renal failure, hypertension, and elderly.This is the first large study showing that among patients undergoing coronary angiography or percutaneous interventions elevated uric acid level is independently associated with an increased risk of CIN.
- Association of Medicare Part D Low-Income Cost Subsidy Program Enrollment with Increased Fill Adherence to Clopidogrel After Coronary Stent Placement. [JOURNAL ARTICLE]
- Pharmacotherapy 2014 Oct 14.
To determine the association between enrollment in the Medicare Part D low-income subsidy (LIS) program, which reduces out-of-pocket medication costs, and fill adherence to the antiplatelet drug clopidogrel after coronary stent placement.Retrospective cohort study.Pharmacy claims database of a large national Medicare Part D insurer.We selected a total of 2967 beneficiaries of a national Medicare Part D plan who had a coronary stent placed between April and December 2006 and were prescribed clopidogrel but were not preexisting users of clopidogrel. Of these patients, 504 were enrolled in the LIS program and 2463 were not.We defined LIS status as enrollment in the LIS program at any point during the 12 months after the procedure. We examined the association between LIS status and good medication fill adherence to clopidogrel, defined as proportion of days covered of 80% or more, or discontinuation of clopidogrel over the 12-month window starting from the date of their stent placement. We also identified patients with claims-based diagnoses of major bleeding events while taking clopidogrel. For those patients, we calculated fill adherence only for the period between medication initiation and the onset of major bleeding and/or did not classify them as having inappropriately discontinued the medication. We created a propensity score predicting the propensity of being eligible for the LIS benefit and used inverse propensity score weighting with regression adjustment to generate estimates of the effect parameters. LIS enrollment was associated with a higher predicted likelihood of good clopidogrel fill adherence after stent placement (54.8% for LIS enrollees vs 47.6% for nonenrollees; p=0.008). No significant difference was noted between the two groups in predicted risk of discontinuing clopidogrel after stent placement (18.3% for LIS enrollees vs 21.0% for nonenrollees; p=0.21).The LIS benefit was associated with better clopidogrel fill adherence after stent placement. Although clopidogrel is now available in generic form, our work underscores the need for efforts to identify and enroll patients in the LIS benefit who require costly antiplatelet medications for coronary heart disease.
- Non-antiplatelet effect of Clopidogrel: Improving endothelial function in Chinese healthy subjects with different CYP2C19 genotype. [JOURNAL ARTICLE]
- Clin Exp Pharmacol Physiol 2014 Oct 14.
Clopidogrel has been demonstrated to improve endothelial function in vitro and in patients with coronary artery disease (CAD). But it remains unclear whether such an effect of clopidogrel is associated with CYP2C19 polymorphisms which determines the antiplatelet effect of clopidogrel.After genotyping, 12 healthy subjects were enrolled in our study. Among them, 6 subjects were CYP2C19*1/*1(extensive metabolisers, EMs) and the other 6 subjects were CYP2C19*2/*2or*3 (poor metabolisers, PMs). All subjects received 300mg clopidogel orally. Endothelial function was assessed by measurement of flow-mediated dilation (FMD) of the brachial artery and ADP-induced platelet aggregation was determined by using optical aggregometry at 0h, 4h, and 24h after administration of 300mg clopidogrel.FMD was significantly higher at 4h and 24h after a loading-dose administration of clopidogrel in both CYP2C19 EMs and PMs groups, but showed no significant difference between the two groups. ADP-induced platelet aggregation was signifcantly inhibited at 4h and 24h after administration of clopidogrel in CYP2C19 EM group. However, there was no statistical correlation between the change in FMD and ADP-induced platelet aggregation in the two CYP2C19 groups.It is the first time to report that clopidogrel improves endothelial function in healthy Chinese subjects, which is irrelated with CYP2C19 genotype and independent of antiplatelet action. This article is protected by copyright. All rights reserved.
- Dental extractions and risk of bleeding in patients taking single and dual antiplatelet treatment. [JOURNAL ARTICLE]
- Br J Oral Maxillofac Surg 2014 Oct 10.
Our aim was to evaluate the effects of single and dual antiplatelet treatment on postoperative bleeding in patients having dental extractions. The prospective clinical study included 160 patients who were taking antiplatelet drugs. The first group (n=43) were taking 2 drugs, mostly aspirin and clopidogrel, and the second group (n=117) were taking a single antiplatelet drug in the form of aspirin (n=84), clopidogrel (n=20), and ticlopidine (n=13). All patients had simple dental extractions, and local haemostasis was with resorbable collagen sponges, without suturing of the wound. The control group comprised 105 healthy subjects with a similar number of dental extractions. Bleeding was an "event" if it continued for more than 12h, made the patient call or return to the dental practice or emergency department, induced a large haematoma or ecchymosis within the oral soft tissues, or required blood transfusion. A total of 110 teeth were extracted on 59 occasions in the dual drug group, and 232 teeth on 128 occasions in the single drug group. Bleeding was recorded after extraction in only one patient on dual aspirin-clopidogrel treatment, which was mild and easily controlled by local haemostasis. The incidence of postoperative bleeding did not differ significantly among the three groups (χ(2)=4.3, p=0.11). However, the wound was sutured to achieve effective initial local haemostasis in 4/59 (6.8%) and 2/128 (1.6%) occasions of tooth extractions in the dual and single drug groups, respectively, and none in the control group (χ(2)=10.02, p=0.007). Patients taking single or dual antiplatelet drugs may have teeth extracted safely without interruption of treatment using only local haemostatic measures.
- Dendrimer-like assemblies based on organoclays as multi-host system for sustained drug delivery. [JOURNAL ARTICLE]
- Eur J Pharm Biopharm 2014 Oct 9.
Chemical modification of nanoclay will ensure further progress on these materials. In this work, we show that montmorillonite (MTM) nanosheets can be modified with β-cyclodextrin (CD) via a nucleophilic substitution reaction between mono-6- (p-toluenesulfonyl)-6-deoxy-β-CD and an amino group of 3-aminopropyltriethoxysilane (APTES)-functionalized MTM, The resulting MTM-APTES-CD can be further self-assembled into dendrimer-like assemblies, exhibit a well-dispersed property even in Dulbecco's phosphate-buffered saline and do not aggregate for a period of at least 20 days. The structure, morphology and assembly mechanism are systematically studied by (29)Si MAS NMR, FT-IR, (1)HNMR, SEM, FE-TEM, DLS and AFM, and the change in assemblies during the drug release are monitored using FE-TEM images. MTT assays indicate that the assemblies only have low cytotoxicity, while CLSM and TEM observations reveal that the assemblies can easily penetrate cultured human endothelial cells. When clopidogrel is used as a guest molecule, the assemblies show not only much higher loading capacities compared to MTM and other containing β-CD assemblies or nanoparticles, but also a sustained release of clopidogrel up to 30 days. This is attributed to the fact that the guest molecule is both supramolecularly complexed within the dendritic scaffold and intercalated into CD and MTM hosts. Host-guest systems between assemblies and various guests hold promising applications in drug delivery system and in the biomedical fields.