36 results on '"Judge, Heather M."'
Search Results
2. Ticagrelor potentiates adenosine-induced stimulation of neutrophil chemotaxis and phagocytosis
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Alsharif, Khalaf F., Thomas, Mark R., Judge, Heather M., Khan, Haroon, Prince, Lynne R., Sabroe, Ian, Ridger, Victoria C., and Storey, Robert F.
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- 2015
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3. Study of Two Dose Regimens of Ticagrelor Compared With Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease
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Orme, Rachel C., Parker, William A.E., Thomas, Mark R., Judge, Heather M., Baster, Kathleen, Sumaya, Wael, Morgan, Kenneth P., McMellon, Hannah C., Richardson, James D., Grech, Ever D., Wheeldon, Nigel M., Hall, Ian R., Iqbal, Javaid, Barmby, David, Gunn, Julian P., Storey, Robert F., Wilcox (chair), Robert G., Walsh, John T., Smith, William, and Skene, Allan
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- 2018
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4. Vessel wall, not platelet, P2Y12 potentiates early atherogenesis
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West, Laura E., Steiner, Tanja, Judge, Heather M., Francis, Sheila E., and Storey, Robert F.
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- 2014
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5. Prolonged enoxaparin therapy compared with standard-of-care antithrombotic therapy in opiate-treated patients undergoing primary percutaneous coronary intervention.
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Sumaya, Wael, Parker, William A.E., Judge, Heather M., Hall, Ian R., Orme, Rachel C., Adam, Zulfiquar, Richardson, James D., Rothman, Alexander M.K., Morgan, Kenneth P., Gunn, Julian P., and Storey, Robert F.
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FIBRINOLYTIC agents ,PERCUTANEOUS coronary intervention ,ENOXAPARIN ,TRANSLUMINAL angioplasty ,COFFEE grounds ,INTRAVENOUS therapy - Abstract
A novel enoxaparin regimen consisting of intra-arterial bolus (0.75 mg/kg) followed by intravenous infusion (0.75 mg/kg/6 hours) has been developed as a possible solution to the delayed absorption of oral P2Y
12 inhibitors in opiate-treated ST-elevation myocardial infarction (STEMI) patients undergoing primary angioplasty. We aimed to study the feasibility of this regimen as an alternative to standard-of-care treatment (SOC) with unfractionated heparin ± glycoprotein IIb/IIIa antagonist (GPI). One hundred opiate-treated patients presenting with STEMI and accepted for primary angioplasty were randomized (1:1) to either enoxaparin or SOC. Fifty patients were allocated enoxaparin (median age 61, 40% females) and 49 allocated SOC (median age 62, 22% females). One developed stroke before angiography and was withdrawn. One SOC patient had a gastrointestinal bleed resulting in 1 g drop in hemoglobin and early cessation of GPI infusion. Two enoxaparin patients had transient minor bleeding: one transient gingival bleed and one episode of coffee ground vomit with no hemoglobin drop or hemodynamic instability. Two SOC and no enoxaparin group patients had acute stent thrombosis. These preliminary data support further study of this novel 6-hour enoxaparin regimen in opiate-treated PPCI patients. [ABSTRACT FROM AUTHOR]- Published
- 2021
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6. Offset of ticagrelor prior to coronary artery bypass graft surgery for acute coronary syndromes: effects on platelet function and cellular adenosine uptake.
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Ow, Kok Weng, Parker, William A.E., Porter, Mark M., Hanson, Jessica, Judge, Heather M., Briffa, Norman P., Thomas, Mark R., and Storey, Robert F.
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CORONARY artery bypass ,ACUTE coronary syndrome ,TRANSPLANTATION of organs, tissues, etc. ,PLATELET function tests ,BLOOD platelets ,HIGH performance liquid chromatography - Abstract
Ticagrelor is an antagonist of both platelet adenosine diphosphate (ADP) receptor P2Y
12 and equilibrative nucleoside transporter-1. Optimal timing of ticagrelor cessation prior to coronary artery bypass grafting (CABG) remains unclear. We characterized the offset of ticagrelor's effects on platelets and cellular adenosine uptake in ticagrelor-treated patients (n = 13) awaiting CABG. Blood was drawn prior to CABG at multiple timepoints 2 to 120 (h) after the last dose of ticagrelor. Platelet function (n = 13) was assessed with multiple electrode aggregometry (MEA), expressed as arbitrary units (U) derived from area-under-the-curve (AUC) in response to ADP, and inhibition of adenosine uptake by high-performance liquid chromatography (n = 7). Mean±SD AUC was 20.3 ± 8.2 U (2 h post-ticagrelor), 33.0 ± 18.3U (24 h), 56.6 ± 30.6U (48 h), 61.4 ± 20.2U (72 h), 82.8 ± 24.2U (96 h) and 96.0 ± 15.3U (120 h). There was a significant difference between 72 h and 120 h (p =.007), but not between 96 h and 120 h (p >.99). By 96 h, all patients had AUC >31U, an accepted cutoff below which surgical bleeding risk is increased. Adenosine uptake showed no significant differences between the timepoints. These data suggest it takes 4 days for platelet reactivity to recover sufficiently after cessation of ticagrelor to avoid the excess risk of CABG-related bleeding. Discontinuing ticagrelor had no measurable effect on cellular adenosine uptake. [ABSTRACT FROM AUTHOR]- Published
- 2020
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7. Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome.
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Hanson, Jessica, Stokes, Hannah M., Bridge, Claire M., Shaw, Patricia A., Thorneycroft, Kirstie, Judge, Heather M., Parker, William A.E., Orme, Rachel C., Sumaya, Wael, Storey, Robert F., Petrucci, Giovanna, Rocca, Bianca, Porro, Benedetta, and Ajjan, Ramzi A.
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ASPIRIN ,ACUTE coronary syndrome - Abstract
Higher aspirin doses may be inferior in ticagrelor-treated acute coronary syndrome (ACS) patients and reducing bleeding risk whilst maintaining antithrombotic benefits could improve outcomes. We characterized the pharmacodynamics of a novel dual-antiplatelet-therapy regimen consisting of very-low-dose twice-daily (BD) aspirin with standard-dose ticagrelor. A total of 20 ticagrelor-treated ACS patients entered a randomized crossover to take aspirin 20 mg BD (12-hourly) during one 14-day period and 75 mg once-daily (OD) in the other. After 14 days of treatment, serum thromboxane (TX)B
2 and light-transmittance aggregometry were assessed pre- and 2 h post-morning-dose, bleeding time was measured post-dose, and TXA2 and prostacyclin stable metabolites were measured in urine collected 2 h post-morning-dose. Data are expressed as mean ± SD. After 14 days treatment, serum TXB2 levels were significantly greater 2 h post-dosing with aspirin 20 mg BD vs. 75 mg OD (3.0 ± 3.6 ng/mL vs. 0.8 ± 1.9 ng/mL; p = 0.018) whereas pre-dosing levels were not significantly different (3.5 ± 4.1 ng/mL vs. 2.5 ± 3.1 ng/mL, p = 0.23). 1-mmol/L arachidonic acid-induced platelet aggregation was similarly inhibited by both regimens pre-dose (8.5 ± 14.3% vs. 5.1 ± 3.6%, p = 0.24) and post-dose (8.7 ± 14.2% vs. 6.6 ± 5.3%; p = 0.41). Post-dose bleeding time was shorter with 20 mg BD (680 ± 306 s vs. 834 ± 386 s, p = 0.02). Urinary prostacyclin and TX metabolite excretion were not significantly different. In conclusion, compared to aspirin 75 mg OD, aspirin 20 mg BD provided consistent inhibition of platelet TXA2 release and aggregation, and improved post-dose hemostasis, in ticagrelor-treated ACS patients. Further studies are warranted to assess whether this regimen improves the balance of clinical efficacy and safety. [ABSTRACT FROM AUTHOR]- Published
- 2019
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8. Pharmacodynamic Effects of a 6-Hour Regimen of Enoxaparin in Patients Undergoing Primary Percutaneous Coronary Intervention (PENNY PCI Study).
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Sumaya, Wael, Parker, William A. E., Fretwell, Rebekah, Hall, Ian R., Barmby, David S., Richardson, James D., Iqbal, Javaid, Adam, Zulfiquar, Morgan, Kenneth P., Gunn, Julian P., Mason, Annah E., Judge, Heather M., Gale, Christopher P., Ajjan, Ramzi A., and Storey, Robert F.
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- 2018
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9. Monitoring Antiplatelet Therapy.
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Orme, Rachel, Judge, Heather M., and Storey, Robert F.
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CARDIOVASCULAR disease treatment , *THROMBOSIS , *PLATELET aggregation inhibitors , *ASPIRIN , *PHARMACODYNAMICS , *CLOPIDOGREL - Abstract
The increasing use of antiplatelet therapy, particularly aspirin and oral P2Y12 inhibitors, in the prevention and management of arterial thrombosis, has stimulated extensive pharmacodynamic studies and research into tailored antiplatelet regimens. Many different methodologies have been studied for monitoring antiplatelet drugs and some are now well validated and used in clinical practice. However, clinical studies of tailored antiplatelet therapy have not convincingly demonstrated a benefit of this approach in patients treated with aspirin and clopidogrel, coupled with the fact that more potent antiplatelet therapies have more consistent effects compared with clopidogrel and so may reduce the rationale for monitoring. On the other hand, the optimum timing of urgent surgery after cession of oral antiplatelet therapy may be informed by platelet function testing. This review discusses the differentmethodologies that have been used to monitor the effects of antiplatelet therapy and highlights the current position of platelet function testing in clinical practice. [ABSTRACT FROM AUTHOR]
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- 2017
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10. Cangrelor inhibits the binding of the active metabolites of clopidogrel and prasugrel to P2Y 12 receptors in vitro.
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Judge, Heather M., Buckland, Robert J., Jakubowski, Joseph A., and Storey, Robert F.
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CLOPIDOGREL , *PRASUGREL , *ANTICOAGULANTS , *PLATELET aggregation inhibitors , *METABOLITES - Abstract
Cangrelor is a rapid-acting, direct-binding, and reversible P2Y12antagonist which has been studied for use during percutaneous coronary intervention (PCI) in patients with or without pretreatment with an oral P2Y12antagonist. As cangrelor is administered intravenously, it is necessary to switch to an oral P2Y12antagonist following PCI, such as the thienopyridines clopidogrel, and prasugrel or the non-pyridine ticagrelor. Previous studies have suggested a negative pharmacodynamic interaction between cangrelor and thienopyridines. Thisin vitrostudy evaluated the receptor-level interaction between cangrelor and the active metabolite (AM) of clopidogrel or prasugrel by assessing functional P2Y12receptor number using a33P-2MeSADP binding assay. All P2Y12antagonists studied resulted in strong P2Y12receptor blockade (cangrelor: 93.6%; clopidogrel AM: 93.0%; prasugrel AM: 97.9%). Adding a thienopyridine AM in the presence of cangrelor strongly reduces P2Y12receptor blockade by the AM (clopidogrel AM: 7%, prasugrel AM: 3.2%). The thienopyridine AMs had limited ability to compete with cangrelor for binding to P2Y12(% P2Y12receptor blockade after co-incubation with cangrelor 1000 nmol/L: 11.7% for clopidogrel AM 3 µmol/L; 34.1% for prasugrel AM 3 µmol/L). In conclusion,in vitrocangrelor strongly inhibits the binding of clopidogrel and prasugrel AMs to the P2Y12receptor, consistent with the previous observation of a negative pharmacodynamic interaction. Care may need to be taken to not overlap exposure to thienopyridine AMs and cangrelor in order to reduce the risk of thrombotic complications following PCI. [ABSTRACT FROM PUBLISHER]
- Published
- 2016
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11. Platelet P2Y12 Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model.
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Thomas, Mark R., Outteridge, Samuel N., Ajjan, Ramzi A., Phoenix, Fladia, Sangha, Gurpreet K., Faulkner, Rachael E., Ecob, Rosemary, Judge, Heather M., Khan, Haroon, West, Laura E., Dockrell, David H., Sabroe, Ian, and Storey, Robert F.
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- 2015
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12. PAR1 antagonists inhibit thrombin-induced platelet activation whilst leaving the PAR4-mediated response intact.
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Judge, Heather M., Jennings, Lisa K., Moliterno, David J., Hord, Edward, Ecob, Rosemary, Tricoci, Pierluigi, Rorick, Tyrus, Kotha, Jayaprakash, and Storey, Robert F.
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ACUTE coronary syndrome , *PLATELET aggregation inhibitors , *PROTEASE-activated receptors , *THROMBIN , *PLATELET-rich plasma , *THROMBIN receptors - Abstract
Thrombin-induced platelet activation is initiated by PAR1 and PAR4 receptors. Vorapaxar, a PAR1 antagonist, has been assessed in patients with acute coronary syndromes (ACS) and stable atherosclerotic disease in addition to standard-of-care treatment. In clinical trials, vorapaxar has been observed to reduce the frequency of ischaemic events in some subgroups though in others has increased the frequency of bleeding events. Among patients undergoing CABG surgery, which is associated with excess thrombin generation, bleeding was not increased. The aim of these studies was to investigate the effects of selective PAR1 antagonism on thrombin-induced platelet activation in patients receiving vorapaxar or placebo in the TRACER trial and to explore the roles of PAR1 and PAR4 in thrombin-induced platelet activation in healthy volunteers. ACS patients receiving vorapaxar or placebo in the TRACER trial were studied at baseline and 4 hours, 1 and 4 months during drug administration. Thrombin-induced calcium mobilisation in platelet-rich plasma was assessed by flow cytometry. In vitro studies were performed in healthy volunteers using the PAR1 antagonist SCH79797 or PAR4 receptor desensitisation. Vorapaxar treatment significantly inhibited thrombin-induced calcium mobilisation, leaving a residual, delayed response. These findings were consistent with calcium mobilisation mediated via the PAR4 receptor and were reproduced in vitro using SCH79797. PAR4 receptor desensitization, in combination with SCH79797, completely inhibited thrombin-induced calcium mobilisation confirming that the residual calcium mobilisation was mediated via PAR4. In conclusion vorapaxar selectively antagonises the PAR1-mediated component of thrombin-induced platelet activation, leaving the PAR4-mediated response intact, which may explain why vorapaxar is well tolerated in patients undergoing CABG surgery since higher thrombin levels in this setting may override the effects of PAR1 antagonism through PAR4 activation, thus preserving haemostasis. Further assessment may be warranted. [ABSTRACT FROM AUTHOR]
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- 2015
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13. Evolving pattern of platelet P2Y12 inhibition in patients with acute coronary syndromes.
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Joshi, Rajiv R., Hossain, Rashed, Morton, Allison C., Ecob, Rosemary, Judge, Heather M., Wales, Clare, Walker, Jemma V., Karunakaran, Arun, and Storey, Robert F.
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PLATELET aggregation inhibitors ,CLOPIDOGREL ,PHYSIOLOGICAL effects of aspirin ,TREATMENT of acute coronary syndrome ,CORONARY heart disease treatment ,THERAPEUTICS - Abstract
Dual antiplatelet therapy consisting of clopidogrel in addition to aspirin has previously been the standard of care for patients with acute coronary syndromes (ACS) but international guidelines have been evolving over the last 4 years with the introduction of prasugrel and ticagrelor. In October 2009, prasugrel was approved in the UK by the National Institute of Health and Clinical Excellence (NICE) for use in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), diabetic patients with non-ST-elevation (NSTE) ACS undergoing PCI and patients with stent thrombosis while other ACS patients were to continue receiving clopidogrel. Ticagrelor was approved in October 2011 by NICE for use in patients with moderate-to-high risk NSTE ACS and STEMI undergoing primary PCI and was recommended in preference to clopidogrel in European guidelines. These recommendations were adopted in our region, constituting a population of 1.8 million. We studied the effect of changing patterns of P2Y
12 inhibitor usage on levels of platelet inhibition during maintenance therapy. Patients admitted to Northern General Hospital, Sheffield, with NSTE ACS or STEMI managed with primary PCI were enrolled over two periods of time: May 2010 to November 2011 (T1); and October 2012 to February 2013 (T2). Venous blood samples were obtained at 1 month after the onset of ACS. Light transmittance aggregometry (LTA) was performed and maximum aggregation response to ADP 20 μM was determined. A total of 116 patients were enrolled in T1 of whom 82 were receiving clopidogrel and 34 were receiving prasugrel. Twenty-nine patients were enrolled in T2, all of whom were receiving ticagrelor. Mean LTA results according to treatment with clopidogrel, prasugrel and ticagrelor were 57 ± 18%, 41 ± 20%, and 31 ± 12%, respectively. Prasugrel was associated with significantly lower platelet aggregation responses than clopidogrel ( p < 0.001) and ticagrelor was associated with significantly lower platelet aggregation responses than both prasugrel ( p = 0.015) and clopidogrel ( p < 0.001). We conclude that international guidelines and NICE approval have led to increasing levels of P2Y12 inhibition in ACS patients in this UK centre between May 2010 and February 2013. Ticagrelor was associated with significantly greater P2Y12 inhibition than both clopidogrel and prasugrel during maintenance therapy. [ABSTRACT FROM AUTHOR]- Published
- 2014
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14. Ticagrelor Effectively and Reversibly Blocks Murine Platelet P2Y12-Mediated Thrombosis and Demonstrates a Requirement for Sustained P2Y12 Inhibition to Prevent Subsequent Neointima∗.
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Patil, Shankar B., Jackman, Laura E., Francis, Sheila E., Judge, Heather M., Nylander, Sven, and Storey, Robert F.
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- 2010
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15. The active metabolite of prasugrel effectively blocks the platelet P2Y12 receptor and inhibits procoagulant and pro-inflammatory platelet responses.
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Judge, Heather M., Buckland, Robert J., Sugidachi, Atsuhiro, Jakubowski, Joseph A., and Storey, Robert F.
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METABOLITES , *BLOOD platelets , *CALCIUM , *PHOSPHORYLATION , *ENZYME-linked immunosorbent assay , *VASODILATORS , *FLOW cytometry - Abstract
The aim of these studies was to investigate the extent of platelet P2Y12 receptor inhibition by the thienopyridine active metabolite of prasugrel, R-138727. Blood was taken from healthy volunteers and pre-incubated with R-138727 or cangrelor (AR-C66931MX). Platelet aggregation was assessed in platelet rich plasma (PRP) and whole blood (WB). Vasodilator stimulated phosphoprotein (VASP) phosphorylation, platelet procoagulant activity (annexin V binding and microparticle formation) and calcium mobilisation were measured by flow cytometry. Platelet-leukocyte co-aggregate formation and sCD40L release, both pro-inflammatory responses of platelets, were measured by flow cytometry and ELISA, respectively. P2Y12 receptor antagonism was determined using a radioligand binding assay (33P 2-MeSADP) in resting and stimulated platelets and the effects of clopidogrel administration were also assessed. R-138727 yielded concentration-dependent inhibition of platelet aggregation, VASP phosphorylation inhibition, procoagulant activity and pro-inflammatory responses. In the presence of R-138727 or cangrelor there was increased calcium reuptake following agonist stimulation. R-138727 30 µmol/L and cangrelor 1 µmol/L completely inhibited 33P 2-MeSADP binding, compared to partial inhibition following clopidogrel administration. Platelet activation and granule secretion did not expose an additional pool of P2Y12 receptors. Prasugrel's active metabolite effectively blocks the P2Y12 receptor with the highest concentrations tested yielding complete inhibition of P2Y12-mediated amplification of several important platelet responses. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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16. Common sequence variations in the P2Y 12 and CYP3A5 genes do not explain the variability in the inhibitory effects of clopidogrel therapy.
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Smith, Simon M. G., Judge, Heather M., Peters, Gary, Armstrong, Martin, Fontana, Pierre, Gaussem, Pascale, Daly, Martina E., and Storey, Robert F.
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BLOOD platelets , *GENETIC polymorphisms , *CELL aggregation , *NUCLEOTIDES , *GENES , *HEREDITY - Abstract
The efficacy of the platelet P2Y 12 receptor antagonist clopidogrel, which undergoes cytochrome-mediated metabolism to its active form, shows marked inter-individual variability. We investigated whether polymorphic variations in the P2Y 12 gene, which have been linked to platelet aggregation phenotypes, or the cytochrome P450 3A5 gene 6986G  >  A polymorphism, which largely determines CYP3A5 expression, influence the response to clopidogrel therapy. Fifty-four patients listed for elective percutaneous coronary intervention were studied using ADP-induced optical aggregometry, whole-blood single platelet counting (WBSPC) aggregometry, and flow-cytometric analysis of platelet P-selectin expression and platelet-monocyte conjugate formation. Platelet reactivity was measured at baseline, 4  h post clopidogrel 300  mg, and 10 and 28 days following clopidogrel 75  mg daily. A further 55 patients were studied using ADP-induced WBSPC at baseline and 4  h post clopidogrel 600  mg. Patients were genotyped for P2Y 12 haplotype and the CYP3A5 6986G  >  A single nucleotide polymorphism. Neither genotype was found to significantly influence the inhibition of platelet responses by either clopidogrel regimen. In conclusion, common sequence variations within the P2Y 12 and CYP3A5 genes do not contribute any major effect to the inter-patient variability in clopidogrel efficacy. [ABSTRACT FROM AUTHOR]
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- 2006
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17. Glycoprotein IIb/IIIa and P2Y12 receptor antagonists yield additive inhibition of platelet aggregation, granule secretion, soluble CD40L release and procoagulant responses.
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Judge, Heather M., Buckland, Robert J., Holgate, Carol E., and Storey, Robert F.
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GLYCOPROTEINS , *GLYCOCONJUGATES , *PROTEINS , *BLOOD platelet aggregation , *CELL aggregation , *BLOOD platelets , *BLOOD cells - Abstract
Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists, including abciximab and tirofiban, are administered concurrently with clopidogrel, a P2Y12 antagonist, and aspirin in some patients undergoing percutaneous coronary intervention. We studied the effects of, and interactions between, abciximab, tirofiban, aspirin and the P2Y12 antagonist cangrelor on platelet aggregation, α and dense granule secretion and procoagulant responses in vitro. Blood was obtained from healthy volunteers. Platelet aggregation, dense granulesecretion, α granule secretion (PAI-1 and soluble CD40 ligand levels) and procoagulant responses (annexin-V and microparticle formation) were assessed using collagen and thrombin receptor activating peptide (TRAP) as agonists. All the antagonists used singularly inhibited collagen-induced responses. Combinations of abciximab or tirofiban with aspirin and/or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor. Cangrelor inhibited TRAP-induced responses and, again, there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor. The GPIIb/IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between GPIIb/IIIa antagonists and inhibitors of both P2Y12 receptor activation and, to a lesser extent, thromboxane A2 generation. These interactions are likely to have important influences on the safety and efficacy of combination anti-platelet therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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18. Multiple antiplatelet effects of clopidogrel are not modulated by statin type in patients undergoing percutaneous coronary intervention.
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Smith, Simon M. G., Judge, Heather M., Peters, Gary, and Storey, Robert F.
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BLOOD platelets , *STATINS (Cardiovascular agents) , *BLOOD platelet aggregation , *VASCULAR diseases , *CYTOCHROMES , *HEMATOLOGY - Abstract
We investigated whether statin type or dose influenced the inhibition of platelet function induced by clopidogrel in a prospective, open, parallel group study in patients undergoing elective percutaneous coronary intervention. Patients were taking CYP3A4 metabolised atorvastatin ( n = 20) or simvastatin ( n = 21), non-CYP3A4 metabolised pravastatin ( n = 11) or fluvastatin ( n = 2), or no statin therapy ( n = 5). ADP and TRAP-induced platelet aggregation were measured using optical aggregometry, whole-blood single-platelet counting, and the Ultegra and Plateletworks point-of-care systems. Platelet pro-coagulant activity (annexin V binding and microparticle formation), P-selectin expression and platelet-leukocyte conjugate formation were assessed by flow cytometry. Platelet responses were measured at baseline, 4 h post clopidogrel 300 mg, and after 10 and 28 days with clopidogrel 75 mg daily. Clopidogrel significantly inhibited both ADP and TRAP-induced platelet responses over time, with steady state inhibition achieved by day 10. This was demonstrated by all techniques used. There was no significant effect of statin type or dose on platelet responses by any method at any time-point. In conclusion, statins do not influence the inhibitory effects of clopidogrel on multiple platelet responses, including aggregation, P-selectin expression, platelet-leucocyte conjugate formation and pro-coagulant responses, in patients undergoing elective PCI. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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19. Stability of VerifyNow P2Y12 assay results with citrate anticoagulation as compared to hirudin anticoagulation over 20-min period.
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Sumaya, Wael, Joshi, Rajiv R., Judge, Heather M., Ecob, Rosemary, Morton, Allison C., and Storey, Robert F.
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ANTICOAGULANTS ,HIRUDIN ,CITRATES - Abstract
A letter to the editor is presented about the stability of VerifyNow P2Y12 assay results with citrate anticoagulation as compared to hirudin anticoagulation over a period of 20 minutes.
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- 2015
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20. Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y12 Inhibition.
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Braza-Boïls, Aitana, Barwari, Temo, Gutmann, Clemens, Thomas, Mark R., Judge, Heather M., Joshi, Abhishek, Pechlaner, Raimund, Shankar-Hari, Manu, Ajjan, Ramzi A., Sabroe, Ian, Storey, Robert F., and Mayr, Manuel
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ENDOTOXINS ,ENDOTOXEMIA ,BLOOD platelet activation ,MICRORNA ,MOLECULAR microbiology ,PLATELET aggregation inhibitors - Abstract
There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y
12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor (n = 10), clopidogrel (n = 8) or no drug (n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y12 inhibitors. Sepsis patients with fatal outcomes (n = 12) had reduced miR-150 levels compared with survivors (n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y12 inhibition. While P2Y12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia. [ABSTRACT FROM AUTHOR]- Published
- 2020
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21. Platelet Inhibition With Ticagrelor 60 mg Versus 90 mg Twice Daily in the PEGASUS-TIMI 54 Trial.
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Storey, Robert F., Angiolillo, Dominick J., Bonaca, Marc P., Thomas, Mark R., Judge, Heather M., Rollini, Fabiana, Franchi, Francesco, Ahsan, Arif J., Bhatt, Deepak L., Kuder, Julia F., Steg, Philippe Gabriel, Cohen, Marc, Muthusamy, Rangasamy, Braunwald, Eugene, and Sabatine, Marc S.
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PLACEBOS , *CORONARY heart disease prevention , *MYOCARDIAL infarction , *BLOOD sampling , *PHARMACODYNAMICS , *DRUG dosage , *PHARMACOKINETICS , *ADENOSINES , *BLOOD platelets , *BLOOD platelet aggregation , *COMPARATIVE studies , *DOSE-effect relationship in pharmacology , *LONGITUDINAL method , *RESEARCH methodology , *MEDICAL cooperation , *NEUROTRANSMITTERS , *RESEARCH , *TIME , *EVALUATION research , *TREATMENT effectiveness - Abstract
Background: The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) trial studied 2 doses of ticagrelor, 90 mg twice a day (bid) and 60 mg bid, for long-term prevention of ischemic events in patients with prior myocardial infarction. Both doses similarly reduced the rate of ischemic events versus placebo. The pharmacokinetics and pharmacodynamics of ticagrelor 60 mg bid have not been studied.Objectives: In this study, the authors sought to study the pharmacokinetics and pharmacodynamics for ticagrelor 60 mg compared with 90 mg bid.Methods: A total of 180 patients who received >4 weeks of study medication had blood sampling in the morning pre-maintenance dose and again 2 h post-dose. All patients received aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were determined. P2Y12 inhibition was assessed by the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California) (P2Y12 reaction units [PRU]), light transmittance aggregometry (adenosine diphosphate 5 and 20 μmol/l and arachidonic acid), and vasodilator-stimulated phosphoprotein phosphorylation assays. VerifyNow Aspirin assays and serum thromboxane B2 measurements were performed.Results: Mean pre- and post-dose plasma levels of ticagrelor were 35% and 38% lower, respectively, with 60 mg versus 90 mg. Both doses achieved high levels of platelet inhibition pre- and post-dose, with numerically slightly more variability with 60 mg: mean (SD) pre-dose PRU values were 59 ± 63 and 47 ± 43 for ticagrelor 60 and 90 mg, respectively (p = 0.34). High platelet reactivity, determined as PRU >208, was rare with the 60-mg pre-dose and was absent post-dose. Platelet reactivity pre- and post-dose, as measured by light transmittance aggregometry or vasodilator-stimulated phosphoprotein assays, was numerically but not significantly lower with 90 mg than with 60 mg. Aspirin response was not affected by either dose.Conclusions: Ticagrelor 60 mg bid achieved high levels of peak and trough platelet inhibition in nearly all patients, similar to that with 90 mg bid, helping to explain the efficacy of the lower ticagrelor dose in PEGASUS-TIMI 54. [ABSTRACT FROM AUTHOR]- Published
- 2016
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22. THROMBOINFLAMMATORY RESPONSE TO ON-PUMP CORONARY ARTERY BYPASS GRAFT SURGERY LEADS TO IMPAIRED PLATELET REACTIVITY IN PATIENTS WITH ACUTE CORONARY SYNDROME.
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Elamin, Nadir, Nelson, Thomas, Parker, William, Varian, Frances, Williamson, Georgia, McMellon, Hannah, Hanson, Jessica, Middle, Janet, Bridge, Claire, Judge, Heather M., Briffa, Norman, Hunter, Steven, and Storey, Robert F.
- Subjects
- *
CORONARY artery bypass , *ACUTE coronary syndrome , *CARDIOPULMONARY bypass , *BLOOD platelets - Published
- 2022
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23. TICAGRELOR POTENTIATES NEUTROPHIL PHAGOCYTOSIS VIA INHIBITION OF ADENOSINE REUPTAKE BY ERYTHROCYTES.
- Author
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Thomas, Mark R., Alsharif, Khalaf F., Prince, Lynne R., Ridger, Victoria C., Judge, Heather M., Dockrell, David H., Sabroe, Ian, and Storey, Robert F.
- Subjects
- *
NEUTROPHILS , *PHAGOCYTOSIS , *ADENOSINES , *ERYTHROCYTES , *LUNG infections , *SEPSIS , *CLOPIDOGREL , *DIAGNOSIS - Published
- 2015
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24. Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y 12 Inhibition.
- Author
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Braza-Boïls A, Barwari T, Gutmann C, Thomas MR, Judge HM, Joshi A, Pechlaner R, Shankar-Hari M, Ajjan RA, Sabroe I, Storey RF, and Mayr M
- Subjects
- Adolescent, Adult, Biomarkers, Blood Platelets drug effects, Endotoxemia drug therapy, Gene Expression Regulation, Humans, Male, MicroRNAs blood, Platelet Aggregation Inhibitors pharmacology, Platelet Aggregation Inhibitors therapeutic use, Sepsis blood, Sepsis drug therapy, Sepsis etiology, Young Adult, Blood Platelets metabolism, Circulating MicroRNA, Endotoxemia blood, Endotoxemia etiology, Leukocytes metabolism, MicroRNAs genetics, Platelet Activation, Receptors, Purinergic P2Y metabolism
- Abstract
There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y
12 inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor ( n = 10), clopidogrel ( n = 8) or no drug ( n = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y12 inhibitors. Sepsis patients with fatal outcomes ( n = 12) had reduced miR-150 levels compared with survivors ( n = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y12 inhibition. While P2Y12 inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.- Published
- 2020
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25. Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome.
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Parker WAE, Orme RC, Hanson J, Stokes HM, Bridge CM, Shaw PA, Sumaya W, Thorneycroft K, Petrucci G, Porro B, Judge HM, Ajjan RA, Rocca B, and Storey RF
- Subjects
- Aspirin pharmacology, Female, Hemostasis, Humans, Male, Middle Aged, Platelet Aggregation Inhibitors pharmacology, Acute Coronary Syndrome drug therapy, Aspirin therapeutic use, Platelet Aggregation Inhibitors therapeutic use
- Abstract
Higher aspirin doses may be inferior in ticagrelor-treated acute coronary syndrome (ACS) patients and reducing bleeding risk whilst maintaining antithrombotic benefits could improve outcomes. We characterized the pharmacodynamics of a novel dual-antiplatelet-therapy regimen consisting of very-low-dose twice-daily (BD) aspirin with standard-dose ticagrelor. A total of 20 ticagrelor-treated ACS patients entered a randomized crossover to take aspirin 20 mg BD (12-hourly) during one 14-day period and 75 mg once-daily (OD) in the other. After 14 days of treatment, serum thromboxane (TX)B
2 and light-transmittance aggregometry were assessed pre- and 2 h post-morning-dose, bleeding time was measured post-dose, and TXA2 and prostacyclin stable metabolites were measured in urine collected 2 h post-morning-dose. Data are expressed as mean ± SD. After 14 days treatment, serum TXB2 levels were significantly greater 2 h post-dosing with aspirin 20 mg BD vs. 75 mg OD (3.0 ± 3.6 ng/mL vs. 0.8 ± 1.9 ng/mL; p = 0.018) whereas pre-dosing levels were not significantly different (3.5 ± 4.1 ng/mL vs. 2.5 ± 3.1 ng/mL, p = 0.23). 1-mmol/L arachidonic acid-induced platelet aggregation was similarly inhibited by both regimens pre-dose (8.5 ± 14.3% vs. 5.1 ± 3.6%, p = 0.24) and post-dose (8.7 ± 14.2% vs. 6.6 ± 5.3%; p = 0.41). Post-dose bleeding time was shorter with 20 mg BD (680 ± 306 s vs. 834 ± 386 s, p = 0.02). Urinary prostacyclin and TX metabolite excretion were not significantly different. In conclusion, compared to aspirin 75 mg OD, aspirin 20 mg BD provided consistent inhibition of platelet TXA2 release and aggregation, and improved post-dose hemostasis, in ticagrelor-treated ACS patients. Further studies are warranted to assess whether this regimen improves the balance of clinical efficacy and safety.- Published
- 2019
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26. Consistent platelet inhibition with ticagrelor 60 mg twice-daily following myocardial infarction regardless of diabetes status.
- Author
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Thomas MR, Angiolillo DJ, Bonaca MP, Ajjan RA, Judge HM, Rollini F, Franchi F, Ahsan AJ, Bhatt DL, Kuder JF, Steg PG, Cohen M, Muthusamy R, Sabatine MS, and Storey RF
- Subjects
- Adenosine administration & dosage, Adenosine adverse effects, Adenosine pharmacokinetics, Aged, Biomarkers blood, Blood Platelets metabolism, Cell Adhesion Molecules blood, Diabetes Mellitus diagnosis, Diabetes Mellitus drug therapy, Drug Administration Schedule, England, Female, Florida, Glycated Hemoglobin metabolism, Humans, Hypoglycemic Agents therapeutic use, Insulin therapeutic use, Male, Microfilament Proteins blood, Middle Aged, Myocardial Infarction blood, Myocardial Infarction diagnosis, Phosphoproteins blood, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors adverse effects, Platelet Aggregation Inhibitors pharmacokinetics, Platelet Function Tests, Purinergic P2Y Receptor Antagonists adverse effects, Purinergic P2Y Receptor Antagonists pharmacokinetics, Receptors, Purinergic P2Y12 blood, Receptors, Purinergic P2Y12 drug effects, Risk Factors, Ticagrelor, Time Factors, Treatment Outcome, Adenosine analogs & derivatives, Blood Platelets drug effects, Diabetes Mellitus blood, Myocardial Infarction drug therapy, Platelet Activation drug effects, Platelet Aggregation Inhibitors administration & dosage, Purinergic P2Y Receptor Antagonists administration & dosage
- Abstract
Diabetes increases cardiovascular risk and reduces pharmacodynamic response to some oral antiplatelet drugs. This study aimed to determine whether ticagrelor 60 mg twice daily (bid) provided potent and consistent platelet inhibition in patients with vs without diabetes in the PEGASUS-TIMI 54 platelet function substudy. Out of 180 patients studied, 58 patients were randomised to and had received at least four weeks of ticagrelor 60 mg bid, with 20 (34 %) having diabetes, 58 patients received ticagrelor 90 mg bid, with 12 (21 %) having diabetes, and 64 patients received placebo, with 18 (28 %) having diabetes. Blood was sampled pre- and 2 hours post-maintenance dose. In patients treated with ticagrelor 60 mg bid, on-treatment platelet reactivity to ADP, as determined by light transmission aggregometry (LTA), VerifyNow and VASP, was similar in patients with vs without diabetes (LTA post-dose, ADP 20 µM: 29 ± 14 vs 34 ± 10 %, respectively; p = 0.19). A consistent inhibitory effect of ticagrelor 60 mg bid was observed pre- and post-dose regardless of diabetes status, even in insulin-treated patients. Patients with diabetes did not have an increased incidence of high platelet reactivity in either ticagrelor group. Platelet reactivity was similar in patients with diabetes treated with ticagrelor 60 mg vs 90 mg bid. Pharmacokinetics of ticagrelor were not affected by diabetes status. In conclusion, ticagrelor 60 mg bid is equally effective at reducing platelet reactivity in patients with and without diabetes, yielding a consistently high level of platelet inhibition regardless of diabetes status.
- Published
- 2017
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27. Morphine delays the onset of action of prasugrel in patients with prior history of ST-elevation myocardial infarction.
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Thomas MR, Morton AC, Hossain R, Chen B, Luo L, Shahari NN, Hua P, Beniston RG, Judge HM, and Storey RF
- Subjects
- Aged, Cross-Over Studies, Humans, Intestinal Absorption drug effects, Male, Middle Aged, Percutaneous Coronary Intervention, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors blood, Platelet Aggregation Inhibitors pharmacokinetics, Prasugrel Hydrochloride blood, Prasugrel Hydrochloride pharmacokinetics, ST Elevation Myocardial Infarction blood, ST Elevation Myocardial Infarction surgery, Time Factors, Morphine administration & dosage, Morphine adverse effects, Platelet Aggregation Inhibitors administration & dosage, Prasugrel Hydrochloride administration & dosage, ST Elevation Myocardial Infarction drug therapy
- Abstract
Delays in the onset of action of prasugrel during primary percutaneous coronary intervention (PPCI) have been reported and could be related to the effects of morphine on gastric emptying and subsequent intestinal absorption. The study objective was to determine whether morphine delays the onset of action of prasugrel in patients with a prior history of ST-elevation myocardial infarction (STEMI) treated with PPCI. This was a crossover study of 11 aspirin-treated patients with prior history of STEMI treated with PPCI, for which prasugrel and morphine had been previously administered. Patients were randomised to receive either morphine (5 mg) or saline intravenously followed by 60 mg prasugrel. Blood samples were collected before randomised treatment and over 24 hours after prasugrel administration. The inhibitory effects of prasugrel on platelets were determined using the VerifyNow P2Y12 assay and light transmission aggregometry. Plasma levels of prasugrel and prasugrel active metabolite were measured. Platelet reactivity determined by VerifyNow PRU, VerifyNow % Inhibition and LTA was significantly higher at 30-120 minutes (min) when morphine had been co-administered compared to when saline had been co-administered. Morphine, compared to saline, significantly delayed adequate platelet inhibition after prasugrel administration (158 vs 68 min; p = 0.006). Patients with delayed onset of platelet inhibition also had evidence of delayed absorption of prasugrel. In conclusion, prior administration of intravenous morphine significantly delays the onset of action of prasugrel. Intravenous drugs may be necessary to reduce the risk of acute stent thrombosis in morphine-treated STEMI patients undergoing PPCI.
- Published
- 2016
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28. Platelet P2Y12 Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model.
- Author
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Thomas MR, Outteridge SN, Ajjan RA, Phoenix F, Sangha GK, Faulkner RE, Ecob R, Judge HM, Khan H, West LE, Dockrell DH, Sabroe I, and Storey RF
- Subjects
- Adenosine therapeutic use, Biomarkers blood, Blood Platelets metabolism, Chemotaxis, Leukocyte drug effects, Clopidogrel, Cytokines blood, Endotoxins, England, Female, Fibrin Fibrinogen Degradation Products metabolism, Humans, Inflammation blood, Inflammation chemically induced, Inflammation Mediators blood, Male, Platelet Adhesiveness drug effects, Prospective Studies, Thrombosis blood, Thrombosis chemically induced, Ticagrelor, Ticlopidine therapeutic use, Time Factors, Treatment Outcome, Young Adult, Adenosine analogs & derivatives, Anti-Inflammatory Agents therapeutic use, Blood Platelets drug effects, Inflammation drug therapy, Platelet Aggregation Inhibitors therapeutic use, Purinergic P2Y Receptor Antagonists therapeutic use, Receptors, Purinergic P2Y12 blood, Thrombosis drug therapy, Ticlopidine analogs & derivatives
- Abstract
Objective: Clinical studies suggest that platelet P2Y12 inhibitors reduce mortality from sepsis, although the underlying mechanisms have not been clearly defined in vivo. We hypothesized that P2Y12 inhibitors may improve survival from sepsis by suppressing systemic inflammation and its prothrombotic effects. We therefore determined whether clopidogrel and the novel, more potent P2Y12 inhibitor, ticagrelor, modify these responses in an experimental human model., Approach and Results: We randomized 30 healthy volunteers to ticagrelor (n=10), clopidogrel (n=10), or no antiplatelet medication (controls; n=10). We examined the effect of P2Y12 inhibition on systemic inflammation, which was induced by intravenous injection of Escherichia coli endotoxin. Both P2Y12 inhibitors significantly reduced platelet-monocyte aggregate formation and peak levels of major proinflammatory cytokines, including tumor necrosis factor α, interleukin-6, and chemokine (C-C motif) ligand 2. In contrast to clopidogrel, ticagrelor also significantly reduced peak levels of IL-8 and growth colony-stimulating factor and increased peak levels of the anti-inflammatory cytokine IL-10. In addition, ticagrelor altered leukocyte trafficking. Both P2Y12 inhibitors suppressed D-dimer generation and scanning electron microscopy revealed that ticagrelor also suppressed prothrombotic changes in fibrin clot ultrastructure., Conclusions: Potent inhibition of multiple inflammatory and prothrombotic mechanisms by P2Y12 inhibitors demonstrates critical importance of platelets as central orchestrators of systemic inflammation induced by bacterial endotoxin. This provides novel mechanistic insight into the lower mortality associated with P2Y12 inhibitors in patients with sepsis in clinical studies., (© 2015 American Heart Association, Inc.)
- Published
- 2015
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29. Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy.
- Author
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Storey RF, Kotha J, Smyth SS, Moliterno DJ, Rorick TL, Moccetti T, Valgimigli M, Dery JP, Cornel JH, Thomas GS, Huber K, Harrington RA, Hord E, Judge HM, Chen E, Strony J, Mahaffey KW, Tricoci P, Becker RC, and Jennings LK
- Subjects
- Acute Coronary Syndrome blood, Adenosine Diphosphate metabolism, Aged, Aspirin administration & dosage, Aspirin adverse effects, Biomarkers blood, Blood Platelets physiology, Cells, Cultured, Europe, Female, Follow-Up Studies, Humans, Inflammation Mediators blood, Lactones adverse effects, Male, Middle Aged, North America, Platelet Aggregation drug effects, Pyridines adverse effects, Receptor, PAR-1 antagonists & inhibitors, Receptors, Thrombin metabolism, Acute Coronary Syndrome drug therapy, Blood Platelets drug effects, Lactones administration & dosage, Pyridines administration & dosage
- Abstract
Vorapaxar is an antagonist of the protease activated receptor-1 (PAR-1), the principal platelet thrombin receptor. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial evaluated vorapaxar compared to placebo in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. It was the study's objective to assess the pharmacodynamic effects of vorapaxar versus placebo that included aspirin or a thienopyridine or, frequently, a combination of both agents in NSTE-ACS patients. In a substudy involving 249 patients, platelet aggregation was assessed by light transmittance aggregometry (LTA) in 85 subjects (41 placebo, 44 vorapaxar) using the agonists thrombin receptor activating peptide (TRAP, 15 μM), adenosine diphosphate (ADP, 20 μM), and the combination of collagen-related peptide (2.5 μg/ml) + ADP (5 μM) + TRAP (15 μM) (CAT). VerifyNow® IIb/IIIa and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assays were performed, and platelet PAR-1 expression, plasma platelet/endothelial and inflammatory biomarkers were determined before and during treatment. LTA responses to TRAP and CAT and VerifyNow results were markedly inhibited by vorapaxar. Maximal LTA response to TRAP (median, interquartile range) 2 hours post loading dose: placebo 68% (53-75%) and vorapaxar 3% (2-6%), p<0.0001. ADP inhibition was greater in the vorapaxar group at 4 hours and one month (p<0.01). In contrast to the placebo group, PAR-1 receptor number in the vorapaxar group at one month was significantly lower than the baseline (179 vs 225; p=0.004). There were significant changes in selected biomarker levels between the two treatment groups. In conclusion, vorapaxar caused a potent inhibition of PAR-1-mediated platelet aggregation. Further studies are needed to explore vorapaxar effect on P2Y12 inhibition, PAR-1 expression and biomarkers and its contribution to clinical outcomes.
- Published
- 2014
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30. Evolving pattern of platelet P2Y12 inhibition in patients with acute coronary syndromes.
- Author
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Joshi RR, Hossain R, Morton AC, Ecob R, Judge HM, Wales C, Walker JV, Karunakaran A, and Storey RF
- Subjects
- Adenosine administration & dosage, Adenosine analogs & derivatives, Clopidogrel, Humans, Male, Middle Aged, Percutaneous Coronary Intervention, Platelet Aggregation Inhibitors administration & dosage, Ticagrelor, Ticlopidine administration & dosage, Ticlopidine analogs & derivatives, United Kingdom, Acute Coronary Syndrome blood, Acute Coronary Syndrome therapy, Blood Platelets, Platelet Activation, Receptors, Purinergic P2Y12 blood
- Abstract
Dual antiplatelet therapy consisting of clopidogrel in addition to aspirin has previously been the standard of care for patients with acute coronary syndromes (ACS) but international guidelines have been evolving over the last 4 years with the introduction of prasugrel and ticagrelor. In October 2009, prasugrel was approved in the UK by the National Institute of Health and Clinical Excellence (NICE) for use in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), diabetic patients with non-ST-elevation (NSTE) ACS undergoing PCI and patients with stent thrombosis while other ACS patients were to continue receiving clopidogrel. Ticagrelor was approved in October 2011 by NICE for use in patients with moderate-to-high risk NSTE ACS and STEMI undergoing primary PCI and was recommended in preference to clopidogrel in European guidelines. These recommendations were adopted in our region, constituting a population of 1.8 million. We studied the effect of changing patterns of P2Y12 inhibitor usage on levels of platelet inhibition during maintenance therapy. Patients admitted to Northern General Hospital, Sheffield, with NSTE ACS or STEMI managed with primary PCI were enrolled over two periods of time: May 2010 to November 2011 (T1); and October 2012 to February 2013 (T2). Venous blood samples were obtained at 1 month after the onset of ACS. Light transmittance aggregometry (LTA) was performed and maximum aggregation response to ADP 20 μM was determined. A total of 116 patients were enrolled in T1 of whom 82 were receiving clopidogrel and 34 were receiving prasugrel. Twenty-nine patients were enrolled in T2, all of whom were receiving ticagrelor. Mean LTA results according to treatment with clopidogrel, prasugrel and ticagrelor were 57 ± 18%, 41 ± 20%, and 31 ± 12%, respectively. Prasugrel was associated with significantly lower platelet aggregation responses than clopidogrel (p < 0.001) and ticagrelor was associated with significantly lower platelet aggregation responses than both prasugrel (p = 0.015) and clopidogrel (p < 0.001). We conclude that international guidelines and NICE approval have led to increasing levels of P2Y12 inhibition in ACS patients in this UK centre between May 2010 and February 2013. Ticagrelor was associated with significantly greater P2Y12 inhibition than both clopidogrel and prasugrel during maintenance therapy.
- Published
- 2014
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31. Hirudin anticoagulation allows more rapid determination of P2Y₁₂ inhibition by the VerifyNow P2Y12 assay.
- Author
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Sumaya W, Daly RL, Mehra S, Dhutia AJ, Howgego KE, Ecob R, Judge HM, Morton AC, and Storey RF
- Subjects
- Acute Coronary Syndrome blood, Aged, Antithrombins pharmacology, Area Under Curve, Cations, Clopidogrel, Coronary Angiography methods, Female, Humans, Male, Middle Aged, Myocardial Infarction blood, Piperazines pharmacology, Platelet Function Tests methods, Prasugrel Hydrochloride, Receptors, Purinergic P2Y12 analysis, Sodium Citrate, Thiophenes pharmacology, Ticlopidine analogs & derivatives, Ticlopidine pharmacology, Treatment Outcome, Anticoagulants pharmacology, Citrates pharmacology, Hematologic Tests methods, Hirudins pharmacology, Receptors, Purinergic P2Y12 metabolism
- Abstract
VerifyNow (VN) P2Y12 is a point-of-care assay used to assess response to P2Y12 inhibitors. Sodium citrate (citrate) is the standard anticoagulant used for this assay but requires a pre-incubation period. Hirudin is an alternative anticoagulant for platelet function studies that maintains physiological divalent cation levels. We investigated whether hirudin anticoagulation might allow more rapid testing of P2Y₁₂ inhibition at the time of percutaneous coronary intervention (PCI). Blood was collected from the arterial sheath of aspirin-treated patients undergoing elective, urgent or emergency coronary angiography±PCI and aliquots were anticoagulated with either citrate or hirudin. For each anticoagulant, VN P2Y12 was performed both immediately and after 20 minutes. A total of 98 patients were included in this study following pre-treatment with clopidogrel (n=88), prasugrel (n=6) or no P2Y₁₂ inhibitor (n=4). PRU with hirudin immediately (PRU_H_Imm) and PRU with citrate 20 minutes post sampling (PRU_C_20) were very strongly correlated (R=0.95) though PRU_H_Imm tended to be lower than PRU_C_20 so that optimal correlation was estimated by the equation PRU_H_Imm=0.95xPRU_C_20 (p<0.001). Bland-Altman plots showed good agreement between PRU_H_Imm and (0.95xPRU_C_20). Platelet reactivity was more stable over the studied time course with hirudin as compared to citrate. We therefore conclude that VN P2Y12 with hirudin anticoagulation can be performed more rapidly and results are strongly correlated with delayed citrate measurements. Further studies are warranted to assess the utility of this method for improving clinical outcomes in patients undergoing PCI.
- Published
- 2013
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32. Ticagrelor effectively and reversibly blocks murine platelet P2Y12-mediated thrombosis and demonstrates a requirement for sustained P2Y12 inhibition to prevent subsequent neointima.
- Author
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Patil SB, Jackman LE, Francis SE, Judge HM, Nylander S, and Storey RF
- Subjects
- Adenosine pharmacokinetics, Adenosine pharmacology, Animals, Bleeding Time, Blood Coagulation drug effects, Blood Platelets metabolism, Carotid Artery Injuries metabolism, Carotid Artery Injuries pathology, Carotid Artery, Common drug effects, Carotid Artery, Common pathology, Carotid Stenosis metabolism, Carotid Stenosis pathology, Cell Proliferation drug effects, Disease Models, Animal, Dose-Response Relationship, Drug, Fibrinolytic Agents pharmacokinetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, P-Selectin blood, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors pharmacokinetics, Purinergic P2Y Receptor Antagonists pharmacokinetics, Receptors, Purinergic P2Y12 deficiency, Receptors, Purinergic P2Y12 drug effects, Receptors, Purinergic P2Y12 genetics, Thrombosis blood, Ticagrelor, Tunica Intima drug effects, Tunica Intima pathology, Adenosine analogs & derivatives, Blood Platelets drug effects, Carotid Artery Injuries prevention & control, Carotid Stenosis prevention & control, Fibrinolytic Agents pharmacology, Platelet Aggregation Inhibitors pharmacology, Purinergic P2Y Receptor Antagonists pharmacology, Receptors, Purinergic P2Y12 metabolism, Thrombosis prevention & control
- Abstract
Objective: Our goal was to study the effects of ticagrelor on murine platelet function and thrombosis and characterize the time course of P2Y(12) inhibition required to inhibit neointima formation following vascular injury., Methods and Results: Mice were treated with ticagrelor or vehicle. Platelet aggregation and P-selectin expression were assessed over time, and thrombus formation was assessed in laser-injured cremasteric arterioles of P2Y(12)+/+ and P2Y(12)-/- mice. Neointima formation in FeCl(3)-injured carotid artery was assessed in C57BL/6 mice treated with different regimens of ticagrelor. Ticagrelor inhibited platelet aggregation and P-selectin expression in a dose-dependent, reversible manner. Ticagrelor inhibited thrombus formation to the same extent as seen in P2Y(12)-/- mice. Neointima formation was markedly reduced in mice treated with ticagrelor before and 4 hours after injury (neointima area: control, 39 921±22 749 μm(2), versus ticagrelor, 3705±2600 μm(2); P<0.01), whereas administration of ticagrelor either before injury only or from 4 hours postinjury was ineffective., Conclusions: Ticagrelor effectively and reversibly inhibits P2Y(12)-mediated platelet function and thrombosis in mice. P2Y(12) inhibition is required both at the time of and after injury to effectively inhibit neointima formation. Additional studies are warranted to evaluate the role of P2Y(12) inhibition in preventing restenosis.
- Published
- 2010
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33. Relationship between degree of P2Y12 receptor blockade and inhibition of P2Y12-mediated platelet function.
- Author
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Judge HM, Buckland RJ, Sugidachi A, Jakubowski JA, and Storey RF
- Subjects
- Adult, Blood Platelets immunology, Blood Platelets metabolism, Blood Platelets pathology, Cell Adhesion Molecules biosynthesis, Cell Adhesion Molecules genetics, Cell Separation, Cell-Derived Microparticles metabolism, Cells, Cultured, Coronary Thrombosis prevention & control, Female, Flow Cytometry, Humans, Male, Microfilament Proteins biosynthesis, Microfilament Proteins genetics, P-Selectin biosynthesis, P-Selectin genetics, Phosphoproteins biosynthesis, Phosphoproteins genetics, Platelet Activation drug effects, Radioligand Assay, Receptors, Purinergic P2Y12, Signal Transduction drug effects, Signal Transduction immunology, Anticoagulants pharmacology, Blood Platelets drug effects, Piperazines pharmacology, Receptors, Purinergic P2 metabolism
- Abstract
The thienopyridine P2Y12 receptor antagonists clopidogrel and prasugrel prevent arterial thrombosis and are routinely used following percutaneous coronary intervention. However, the optimal level of P2Y12 blockade to effectively inhibit platelet function is unknown. These studies utilised the active metabolite of prasugrel (R-138727) to achieve a range of P2Y12 blockade in vitro and assessed several aspects of platelet function. Blood from healthy volunteers was incubated with R-138727 (0-10 microM). P2Y12 receptor number was assessed using a 33P-2MeSADP binding assay. Platelet aggregation (PA) was measured by optical aggregometry with ADP 2-20 microM. VASP phosphorylation, annexin V binding, microparticle formation and P-selectin expression were assessed by flow cytometry. Increasing numbers of unblocked receptors were required for a sustained aggregation response with decreasing concentrations of ADP. A P2Y12 receptor blockade of 60-80% resulted in strong inhibition of final PA response, P-selectin expression, microparticle formation and vasodilator-stimulated phosphoprotein (VASP). PA induced by ADP 2 microM and P-selectin expression were particularly sensitive to low levels of receptor blockade whereas the VASP phosphorylation assay was relatively insensitive, requiring 60% receptor blockade to achieve substantial inhibition. Different assays varied in their ability to discriminate particular ranges of P2Y12 blockade and 80% or greater P2Y12 receptor blockade is required for consistently strong inhibition of several aspects of platelet function. These data guide the interpretation of results from different assays used to monitor the effects of P2Y12 receptor antagonists.
- Published
- 2010
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34. Utility of a whole blood single platelet counting assay to monitor the effects of tirofiban in patients with acute coronary syndromes scheduled for coronary intervention.
- Author
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Siotia A, Buckland R, Judge HM, Sastry P, and Storey RF
- Subjects
- Acute Disease, Adult, Aged, Aged, 80 and over, Coronary Angiography, Coronary Disease blood, Coronary Disease therapy, Female, Humans, Male, Middle Aged, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors pharmacology, Platelet Function Tests methods, Prospective Studies, Syndrome, Tirofiban, Tyrosine pharmacology, Tyrosine therapeutic use, Angioplasty, Balloon, Coronary, Coronary Disease drug therapy, Drug Monitoring methods, Platelet Aggregation Inhibitors therapeutic use, Platelet Count, Tyrosine analogs & derivatives
- Abstract
This study aimed to establish the utility of a whole-blood single-platelet counting (WBSPC) assay, a measure of microaggregation, in monitoring the effects of tirofiban, comparing this with optical aggregometry (OA) and the Ultegra TRAP cartridge system (UTC), measures of macroaggregation. Fifty-nine patients with acute coronary syndrome scheduled for coronary angiography +/- angioplasty were studied. WBSPC assay (ADP 0.3-100 microM, Sysmex KX21 analyzer), OA (ADP 20 microM) and UTC were performed: before starting tirofiban; 30 min, 4 and 24 h after starting tirofiban; and 1 and 2 h after stopping tirofiban. Thirty minutes after starting tirofiban, there was substantial inhibition of platelet aggregation (40 +/- 30%; WBSPC, 2 minutes after addition of ADP 30 microM) and this remained stable at 4 and 24 h. OA (86 +/- 17%; inhibition of maximal aggregation, ADP 20 microM) and UTC (93 +/- 7%) showed marked inhibition with less inter-individual variation. There was no significant correlation between OA and UTC results (R(2) = 0.006), but fair correlation between OA and WBSPC results (R(2) = 0.37). Greater inhibition of macroaggregation (OA and UTC) was seen compared to microaggregation (WBSPC) such that WBSPC was more discriminating in the therapeutic range when macroaggregation was often completely inhibited. A WBSPC assay of platelet microaggregation shows promise for monitoring GPIIb/IIIa antagonists.
- Published
- 2006
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35. Agonists of toll-like receptor (TLR)2 and TLR4 are unable to modulate platelet activation by adenosine diphosphate and platelet activating factor.
- Author
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Ward JR, Bingle L, Judge HM, Brown SB, Storey RF, Whyte MK, Dower SK, Buttle DJ, and Sabroe I
- Subjects
- Adenosine Diphosphate metabolism, Antibodies, Atherosclerosis metabolism, Blood Platelets metabolism, Calcium metabolism, Cell Line, Epinephrine pharmacology, Humans, Lipopolysaccharides pharmacology, Lipoproteins pharmacology, Megakaryocytes cytology, P-Selectin metabolism, Platelet Activating Factor metabolism, Platelet Membrane Glycoprotein IIb immunology, Platelet Membrane Glycoprotein IIb metabolism, Toll-Like Receptor 2 agonists, Toll-Like Receptor 2 immunology, Toll-Like Receptor 4 agonists, Toll-Like Receptor 4 immunology, Vasoconstrictor Agents pharmacology, Adenosine Diphosphate pharmacology, Platelet Activating Factor pharmacology, Platelet Activation drug effects, Toll-Like Receptor 2 metabolism, Toll-Like Receptor 4 metabolism
- Abstract
Inappropriate platelet activation is a feature of acute and chronic diseases such as disseminated intravascular coagulation (DIC) and atherosclerosis. Since proinflammatory microbial-derived agonists can be involved in the pathogenesis of these diseases, we examined the potential role of TLR4 (mediating responses to LPS) and TLR2 (which responds to bacterial lipopeptides) in platelet activation. Our data suggested low-level expression of TLR2 and TLR4 on platelets, determined by flow cytometry, and we also observed expression of TLR4 on a megakaryocytic cell line by both flow cytometry and immunohistochemistry. Stimulation of the platelets with the TLR4 agonist LPS, and the synthetic TLR2 agonist Pam3CSK4, resulted in no platelet aggregation, no increase in CD62P surface expression and no increase in the cytosolic concentration of Ca2+. The TLR agonists were also unable to directly activate platelets primed with epinephrine, or pretreated with a low concentration of ADP or PAF. Pretreatment of platelets with LPS or Pam3CSK4 also failed to modulate the platelet response to submaximal concentrations of the classical platelet agonists ADP and PAF. We conclude that the TLR agonists LPS and Pam3CSK4 have no direct effect on platelet activation and that platelet TLRs may be a remnant from megakaryocytes. TLR2 and TLR4 agonists are thought to have a significant role in diseases such as atherosclerosis and DIC, but our research suggests that this is through a mechanism other than direct platelet activation or by modification of platelet responses to other agonists.
- Published
- 2005
36. Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation by clopidogrel and the P2Y12 receptor antagonist AR-C69931MX but not aspirin.
- Author
-
Storey RF, Judge HM, Wilcox RG, and Heptinstall S
- Subjects
- Adenosine Diphosphate pharmacology, Adenosine Monophosphate pharmacology, Adenosine Monophosphate therapeutic use, Aspirin pharmacology, Aspirin therapeutic use, Cell Adhesion drug effects, Clopidogrel, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Myocardial Ischemia blood, Myocardial Ischemia drug therapy, P-Selectin analysis, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors therapeutic use, Purinergic P2 Receptor Antagonists, Receptors, Purinergic P2Y12, Stents, Ticlopidine analogs & derivatives, Ticlopidine pharmacology, Ticlopidine therapeutic use, Adenosine Monophosphate analogs & derivatives, Blood Platelets drug effects, Leukocytes drug effects, Membrane Proteins, P-Selectin drug effects, Platelet Aggregation Inhibitors pharmacology
- Abstract
Platelet-leukocyte interactions are recognised to have pro-inflammatory effects, which may be important in the pathophysiology of ischaemic heart disease. Clopidogrel and the novel intravenous antithrombotic agent AR-C69931MX act at the level of the platelet P2Y12 receptor, which is known to amplify platelet activation, aggregation and other responses induced by numerous platelet agonists. We studied the effects of clopidogrel and aspirin on ADP-induced platelet-leukocyte conjugate formation and P-selectin expression in healthy volunteers. The effects of clopidogrel and AR-C69931MX administered to patients with ischaemic heart disease were also assessed. AR-C69931MX and aspirin were also studied in vitro. Clopidogrel and AR-C69931MX suppressed ADP-induced platelet aggregation, P-selectin expression and platelet-leukocyte conjugate formation whereas aspirin had no inhibitory effect. These effects of clopidogrel and AR-C69931MX may confer therapeutic benefits in the management of acute coronary syndromes.
- Published
- 2002
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