The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
Pamela B. Conley - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic and Pharmacodynamic Effects of Elinogrel Results of the Platelet Function Substudy From the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention Patient
Circulation. Cardiovascular interventions, 2012Co-Authors: Dominick J. Angiolillo, Pamela B. Conley, Robert C. Welsh, Janusz Kochman, Matthew W. Mcclure, Dietmar Trenk, Franz-josef Neumann, Gillian Stephens, Lisa K. Jennings, Paul A. GurbelAbstract:Background—Elinogrel is the only selective, competitive and reversible platelet P2Y12 inhibitor available in both intravenous (IV) and oral formulations. Methods and Results—This substudy of the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention patients (INNOVATE-PCI) trial evaluated the pharmacokinetic and pharmacodynamic effects of two dosing regimens of IV followed by oral Elinogrel (120 mg IV plus 100 mg oral twice daily; 120 mg IV plus 150 mg oral twice daily) versus standard clopidogrel therapy (300–600 mg oral loading dose plus 75 mg oral maintenance dose) in 56 patients undergoing nonurgent PCI. At time of randomization, 71.4% (40/56) of patients were using maintenance clopidogrel therapy. In the acute phase, an IV bolus of Elinogrel achieved more rapid and potent antiplatelet effects compared with clopidogrel, which were sustained during the transition from the IV to the oral formulation in the first 24 hours of ...
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A Clopidogrel-Insensitive Inducible Pool of P2Y12 Receptors Contributes to Thrombus Formation: Inhibition by Elinogrel, a Direct-Acting, Reversible P2Y12 Antagonist
The Journal of pharmacology and experimental therapeutics, 2011Co-Authors: Helena Haberstock-debic, Patrick Andre, Scott Mills, David Phillips, Pamela B. ConleyAbstract:It is known that hepatic metabolism limits the antiaggregatory activity of clopidogrel and, as a consequence, its clinical benefits. In this study, we investigated whether other factors exist that could account for clopidogrel's suboptimal antithrombotic activity. Using an in vivo murine FeCl(3) thrombosis model coupled with intravital microscopy, we found that at equivalent, maximal levels of inhibition of ADP-induced platelet aggregation, clopidogrel (50 mg/kg p.o.) failed to reproduce the phenotype associated with P2Y(12) deficiency. However, Elinogrel (60 mg/kg p.o.), a direct-acting reversible P2Y(12) antagonist, achieved maximal levels of inhibition in vivo, and its administration (1 mg/kg i.v.) abolished residual thrombosis associated with clopidogrel dosing. Because Elinogrel is constantly present in the plasma, whereas the active metabolite of clopidogrel exists for ∼2 h, we evaluated whether an intracellular pool of P2Y(12) exists that would be inaccessible to clopidogrel and contribute to its limited antithrombotic activity. Using saturation [(3)H]2-(methylthio)ADP ([(3)H]2MeSADP) binding studies, we first demonstrated that platelet stimulation with thrombin and convulxin (mouse) and thrombin receptor activating peptide (TRAP) (human) significantly increased surface expression of P2Y(12) relative to that of resting platelets. We next found that clopidogrel dose-dependently inhibited ADP-induced aggregation, signaling (cAMP), and surface P2Y(12) on resting mouse platelets, achieving complete inhibition at the highest dose (50 mg/kg), but failed to block this inducible pool. Thus, an inducible pool of P2Y(12) exists on platelets that can be exposed upon platelet activation by strong agonists. This inducible pool is not blocked completely by clopidogrel, contributes to thrombosis in vivo, and can be blocked by Elinogrel.
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THIENOPYRIDINES, BUT NOT Elinogrel, RESULT IN OFF-TARGET EFFECTS AT THE VESSEL WALL THAT CONTRIBUTE TO BLEEDING
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Patrick Andre, Francis Deguzman, Helena Haberstock-debic, Scott Mills, Mayuko Inagaki, Anjali Pandey, Stanley J. Hollenbach, David R. Phillips, Pamela B. ConleyAbstract:Clinical studies with clopidogrel or prasugrel show that although increased inhibition of P2Y 12 and platelet function improves efficacy, bleeding is also increased. Other preclinical and clinical studies have suggested a greater therapeutic index (TI) with reversible inhibitors and disproportionate effects of thienopyridines on bleeding at high doses. We used multiple in vivo (FeCl 3 -induced arterial thrombosis in mesenteric arteries, blood loss after tail transsection, and platelet deposition and wound closure time in a micropuncture model in mesenteric veins) and ex vivo (light transmittance aggregometry, prothrombin time, and activated partial thromboplastin time) mouse models to 1) compare the TI of clopidogrel, prasugrel, and Elinogrel, a reversible, competitive antagonist, with that in P2Y 12 (−/−) mice and 2) determine whether the bleeding consequences of the thienopyridines are attributed only to the inhibition of P2Y 12 . Data indicated greater (Elinogrel) and decreased (thienopyridines) TI compared with that in P2Y 12 (−/−) mice. The impaired TI associated with the thienopyridines was not attributed to non-P2Y 12 activities on platelet function or coagulation but was related to a direct effect at the vessel wall (inhibition of vascular tone). Further analysis showed that the prasugrel off-target effect was dose- and time-dependent and of a reversible nature. In conclusion, the TI of thienopyridines in the mouse may be decreased by P2Y 12 -independent off-target effects at the vessel wall, whereas that of Elinogrel may be enhanced by the reversible, competitive nature of the antiplatelet agent.
Victor L. Serebruany - One of the best experts on this subject based on the ideXlab platform.
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Dyspnea and reversibility of antiplatelet agents: ticagrelor, Elinogrel, cangrelor, and beyond.
Cardiology, 2013Co-Authors: Victor L. Serebruany, Dirk Sibbing, James J. DinicolantonioAbstract:Context: Oral reversible platelet P2Y12 receptor inhibitors (ticagrelor and Elinogrel) cause double-digit rates of dyspnea, while irreversible oral antiplatelet d
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Prasugrel The Real-Life Perspective
Circulation. Cardiovascular quality and outcomes, 2013Co-Authors: Victor L. Serebruany, Dan AtarAbstract:The unequivocal importance of platelet inhibition for prevention of secondary occlusive vascular events in patients with coronary heart disease is well established. Yet the scientific debates on the preferred agents for platelet inhibition have reached new heights. Recent antiplatelet clinical trials, such as Aspirin and Clopidogrel Compared With Clopidogrel Alone After Recent Ischaemic Stroke or Transient Ischaemic Attack in High-Risk Patients (MATCH),1 Clopidogrel and Aspirin Versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA),2 Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel (TRITON),3 and Platelet Inhibition and Patient Outcomes (PLATO),4 have raised concerns with regard to vascular antithrombotic efficacy in the investigated, more potent combination antiplatelet regimens, which at the same time increase the bleeding risks. In a different conceptual approach, researchers have attempted to link high-risk cohorts and worsened clinical outcomes to the degree of platelet inhibition by individual tailoring of antiplatelet therapy. However, trials, such as the Gauging Responsiveness With A VerifyNow Assay—Impact on Thrombosis And Safety (GRAVITAS),5 Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel (TRIGGER-PCI),6 Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention Patients (INNOVATE-PCI),7 Assessment by a Double …
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Viewpoint: Reversible nature of platelet binding causing transfusion-related acute lung injury (TRALI) syndrome may explain dyspnea after ticagrelor and Elinogrel
Thrombosis and haemostasis, 2012Co-Authors: Victor L. SerebruanyAbstract:There may be a universal mechanism explaining dyspnea after ticagrelor and Elinogrel, namely, transfusion-related acute lung injury (TRALI). Indeed, recent clinical trials with ticagrelor (DISPERSE, DISPERSE-II, and PLATO), and Elinogrel (INNOVATE PCI) revealed double-digit rates of dyspnea after novel reversible antiplatelet agents. In contrast, dyspnea is not associated with conventional non-reversible agents such as aspirin, or thienopyridines (ticlopidine, clopidogrel, or prasugrel) suggesting distinct mechanism of shortness of breath after ticagrelor and Elinogrel. The adenosine hypothesis has been offered to explain such adverse association. However, despite obvious similarity between ticagrelor and adenosine molecules, the chemical structure of Elinogrel is entirely different. In fact, ticagrelor is a cyclopentyl-triazolo-pyrimidine, while Elinogrel is a quinazolinedione. Since both agents cause dyspnea, the adenosine hypothesis is no longer valid. In contrast, the reversible nature of platelet inhibition attributable to both ticagrelor and Elinogrel causing premature cell ageing, apoptosis, impaired turnover due to sequestration of overloaded, exhausted platelets in the pulmonary circulation are among potential autoimmune mechanism(s) resulting in the development of a TRALI-like reaction, and frequent dyspnea. Despite expected benefit for better bleeding control, further development of reversible antithrombins is severely limited due to the existence of a potentially universal serious adverse event, such as TRALI-syndrome with dyspnea as a predominant clinical manifestation. Since TRALI is an established number one contributor to mortality after blood transfusions, ticagrelor death “benefit” in PLATO is challenged further.
Denise E. Jackson - One of the best experts on this subject based on the ideXlab platform.
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P2Y_12 receptor: platelet thrombus formation and medical interventions
International Journal of Hematology, 2012Co-Authors: Fatemeh Moheimani, Denise E. JacksonAbstract:Platelets express a wide range of receptors and proteins that play essential roles in thrombus formation. Among these, the P2Y_12 receptor, a member of the G protein-coupled receptor family, has attracted a significant amount of attention. Stimulation of the P2Y_12 receptor by ADP results in activation of various signaling pathways involved in amplification of platelet activation and aggregation. There have been extensive attempts to design an ideal antithrombotic agent to block P2Y_12, which shows selective expression, as an intervention for cardiovascular disease. Current inhibitors of the P2Y_12 receptor include indirect inhibitor members of the thienopyridine family (ticlopidine, clopidogrel, and prasugrel), and direct P2Y_12 inhibitors (ticagrelor, cangrelor and Elinogrel). Of these, clopidogrel is the most commonly prescribed P2Y_12 blocker; however, this product does not fulfill the ideal therapeutic requirements. The main limitations of clopidogrel administration include slow onset, prevention of recovery of platelet functions, and interindividual variability. Hence, advanced studies have been carried out to achieve more efficient and safer P2Y_12 blockade. In this review, we provide a brief but comprehensive report on P2Y_12, its role on platelet thrombus formation, and the targeting of this receptor as an intervention for cardiovascular disease, for the benefit of basic science and clinical researchers.
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P2Y12 receptor: platelet thrombus formation and medical interventions.
International journal of hematology, 2012Co-Authors: Fatemeh Moheimani, Denise E. JacksonAbstract:Platelets express a wide range of receptors and proteins that play essential roles in thrombus formation. Among these, the P2Y12 receptor, a member of the G protein-coupled receptor family, has attracted a significant amount of attention. Stimulation of the P2Y12 receptor by ADP results in activation of various signaling pathways involved in amplification of platelet activation and aggregation. There have been extensive attempts to design an ideal antithrombotic agent to block P2Y12, which shows selective expression, as an intervention for cardiovascular disease. Current inhibitors of the P2Y12 receptor include indirect inhibitor members of the thienopyridine family (ticlopidine, clopidogrel, and prasugrel), and direct P2Y12 inhibitors (ticagrelor, cangrelor and Elinogrel). Of these, clopidogrel is the most commonly prescribed P2Y12 blocker; however, this product does not fulfill the ideal therapeutic requirements. The main limitations of clopidogrel administration include slow onset, prevention of recovery of platelet functions, and interindividual variability. Hence, advanced studies have been carried out to achieve more efficient and safer P2Y12 blockade. In this review, we provide a brief but comprehensive report on P2Y12, its role on platelet thrombus formation, and the targeting of this receptor as an intervention for cardiovascular disease, for the benefit of basic science and clinical researchers.
Karsten Schrör - One of the best experts on this subject based on the ideXlab platform.
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'Reversible nature of platelet binding causing transfusion-related acute lung injury (TRALI) syndrome may explain dyspnea after ticagrelor and Elinogrel' - a hypothesis that remains unproven.
Thrombosis and haemostasis, 2012Co-Authors: Karsten SchrörAbstract:'Reversible nature of platelet binding causing transfusion-related acute lung injury (TRALI) syndrome may explain dyspnea after ticagrelor and Elinogrel' – a hypothesis that remains unproven - Editorial on Serebruany: ‘Viewpoint: Reversible nature of platelet binding causing transfusion-related acute lung injury (TRALI) syndrome may explain dyspnea after ticagrelor and Elinogrel’ (Thromb Haemost 2012; 108.6)
C. Michael Gibson - One of the best experts on this subject based on the ideXlab platform.
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Newer Pharmaceutical Agents for STEMI Interventions
Interventional cardiology clinics, 2012Co-Authors: Anjan K. Chakrabarti, Shalin J. Patel, Robert L. Salazar, Lakshmi Gopalakrishnan, Varun Kumar, Ujjwal Rastogi, Priyamvada Singh, Cafer Zorkun, C. Michael GibsonAbstract:Pharmaceutical agents currently used in clinical practice for early management of ST elevation myocardial infraction (STEMI) act primarily on the two pathways of clot formation: platelet aggregation and the coagulation cascade. Although percutaneous coronary intervention is the standard therapy for revascularization, new fibrinolytic drugs are being developed to provide increased safety and efficacy through a longer plasma half-life, more fibrin specificity, and resistance to plasminogen activator inhibitor-1. Antiplatelet therapies useful for early and extended management of STEMI include acetylsalicylic acid, glycoprotein IIb/IIIa inhibitors (eptifibatide, tirofiban, and abciximab), the thienopyridines (clopidogrel and prasugrel), and contemporary agents (ticagrelor, cangrelor, Elinogrel, and vorapaxar). Novel therapies for long-term inhibition of thrombin formation following STEMI include factor Xa inhibitors, such as rivaroxaban and apixaban. Emerging areas of STEMI treatment include pharmacotherapy that specifically targets reperfusion injury and cardiomyoplasty, which involves the use of hematopoietic stem cell therapy or growth factors to induce proliferation and differentiation of cardiac myocytes.
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A randomized, double-blind, active-controlled phase 2 trial to evaluate a novel selective and reversible intravenous and oral P2Y 12 inhibitor Elinogrel versus clopidogrel in patients undergoing nonurgent percutaneous coronary intervention: The INNOV
Circulation. Cardiovascular interventions, 2012Co-Authors: Robert C. Welsh, Sunil V. Rao, Uwe Zeymer, Vivian Thompson, Kurt Huber, Janusz Kochman, Matthew W. Mcclure, Daniel D. Gretler, Deepak L. Bhatt, C. Michael GibsonAbstract:Background—We evaluated the safety, efficacy, and tolerability of Elinogrel, a competitive, reversible intravenous and oral P2Y12 inhibitor that does not require metabolic activation, in patients undergoing nonurgent percutaneous coronary intervention. Methods and Results—In a randomized, double-blind, dose-ranging phase 2b trial, 652 patients received either 300 or 600 mg of clopidogrel pre-percutaneous coronary intervention followed by 75 mg daily or 80 or 120 mg of IV Elinogrel followed by 50, 100, or 150 mg oral Elinogrel twice daily. Numerous exploratory safety and efficacy end points were assessed and, as such, had no prespecified primary end point, and the study was not powered to conclusively evaluate its objectives. Thrombolysis in myocardial infarction combined bleeding was increased with Elinogrel (hazard ratio, 1.98; 95% confidence interval, 1.10 to 3.57), related largely to increased bleeding requiring medical attention (Elinogrel 47/408 [11.5%] versus clopidogrel 13/208 [6.3%]) and occurring...
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Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of Elinogrel, a selective and reversible P2Y12-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneo
American heart journal, 2010Co-Authors: Sergio Leonardi, Sunil V. Rao, Uwe Zeymer, Kurt Huber, Janusz Kochman, Deepak L. Bhatt, C. Michael Gibson, Matthew T. Roe, Robert A. Harrington, Mina MadanAbstract:Despite current dual-antiplatelet therapy with aspirin and clopidogrel, adverse clinical events continue to occur during and after percutaneous coronary intervention (PCI). The failure of clopidogrel to provide optimal protection may be related to delayed onset of action, interpatient variability in its effect, and an insufficient level of platelet inhibition. Furthermore, the irreversible binding of clopidogrel to the P2Y 12 receptor for the life span of the platelet is associated with increased bleeding risk especially during urgent or emergency surgery. Novel antiplatelet agents are required to improve management of patients undergoing PCI. Elinogrel is a potent, direct-acting (ie, non-prodrug), selective, competitive, and reversible P2Y 12 inhibitor available in both intravenous and oral formulations. The INNOVATE-PCI study is a phase 2 randomized, double-blind, clopidogrel-controlled trial to evaluate the safety, tolerability, and preliminary efficacy of this novel antiplatelet agent in patients undergoing nonurgent PCI.
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Safety and feasibility of adjunctive antiplatelet therapy with intravenous Elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Earl
American heart journal, 2009Co-Authors: Jeffrey S. Berger, C. Michael Gibson, Matthew T. Roe, Rakhi Kilaru, Cynthia L. Green, Laura G. Melton, James D. Blankenship, D. Christopher Metzger, Christopher B. Granger, Daniel D. GretlerAbstract:Background Inhibition of the P2Y12 ADP-receptor with oral antiplatelet agents given to patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with improved outcomes, but this strategy is limited by the time required for maximal antiplatelet effect after administration. We examined the safety and tolerability of a novel, direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, Elinogrel, versus placebo when administered to STEMI patients before primary PCI. Methods The ERASE MI trial was a pilot, phase IIA, randomized, double-blind, placebo-controlled, dose-escalation study designed to evaluate the safety and tolerability of escalating doses (10, 20, 40, and 60 mg) of Elinogrel administered as a single intravenous bolus before the start of the diagnostic angiogram preceding primary PCI. Patients were randomly assigned in a 1:1 manner to either Elinogrel or placebo within each dosing group; and all patients received a 600-mg clopidogrel loading dose, followed by a second 300-mg clopidogrel loading dose 4 hours after PCI. The major outcome, in-hospital bleeding, was assessed with the Thrombolysis in Myocardial Infarction and Global Strategies to Open Occluded Coronary Arteries bleeding scales. Pre-PCI corrected Thrombolysis in Myocardial Infarction frame count and ST-segment resolution were also evaluated. Results Seventy patients were randomized in the dose-escalation study, but the dose-confirmation phase was not started because the trial was prematurely terminated for administrative reasons. The incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of Elinogrel versus placebo. No differences in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction frame count, or ST resolution were demonstrated between Elinogrel and placebo. Conclusions With the limitations of a small study sample size, this pilot study provided preliminary data on the feasibility and tolerability of escalating doses of a direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, Elinogrel, as an adjunctive therapy for primary PCI for STEMI.