Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived Antiplatelet Therapies.

OBJECTIVE: Aspirin together with thienopyridine P2Y12 inhibitors, commonly clopidogrel, is a cornerstone of antiplatelet therapy. However, many patients receiving this therapy display high on-treatment platelet reactivity, which is a major therapeutic hurdle to the prevention of recurrent thrombotic events. The emergence of uninhibited platelets after thrombopoiesis has been proposed as a contributing factor to high on-treatment platelet reactivity. Here, we investigate the influences of platelet turnover on platelet aggregation in the face of different dual-antiplatelet therapy strategies. APPROACH AND RESULTS: Traditional light transmission aggregometry, cytometry, advanced flow cytometric imaging, and confocal microscopy were used to follow the interactions of populations of platelets from healthy volunteers and patients with stable cardiovascular disease. Newly formed, reticulated platelets overproportionately contributed to, and clustered at, the core of forming aggregates. This phenomenon was particularly observed in samples from patients treated with aspirin plus a thienopyridine, but was absent in samples taken from patients treated with aspirin plus ticagrelor. CONCLUSIONS: Reticulated platelets are more reactive than older platelets and act as seeds for the formation of platelet aggregates even in the presence of antiplatelet therapy. This is coherent with the emergence of an uninhibited subpopulation of reticulated platelets during treatment with aspirin plus thienopyridine, explained by the short pharmacokinetic half-lives of these drugs. This phenomenon is absent during treatment with ticagrelor, because of its longer half-life and ability to act as a circulating inhibitor. These data highlight the important influences of pharmacokinetics on antiplatelet drug efficacies, especially in diseases associated with increased platelet turnover.

Rapid structural characterization of in vivo and in vitro metabolites of tinoridine using UHPLC-QTOF-MS/MS and in silico toxicological screening of its metabolites.

Tinoridine is a nonsteroidal anti-inflammatory drug and also has potent radical scavenger and antiperoxidative activity. However, metabolism of tinoridine has not been thoroughly investigated. To identify in vivo metabolites, the drug was administered to Sprague-Dawley rats (n = 5) at a dose of 20 mg kg(-1), and blood, urine and feces were collected at different time points up to 24 h. In vitro metabolism was delved by incubating the drug with rat liver microsomes and human liver microsomes. The metabolites were enriched by optimized sample preparation involving protein precipitation using acetonitrile, followed by solid-phase extraction. Data processes were carried out using multiple mass defects filters to eliminate false-positive ions. A total of 11 metabolites have been identified in urine samples including hydroxyl, dealkylated, acetylated and glucuronide metabolites; among them, some were also observed in plasma and feces samples. Only two major metabolites were formed using liver microsomal incubations. These metabolites were also observed in vivo. All the 11 metabolites, which are hitherto unknown and novel, were characterized by using ultrahigh-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry in combination with accurate mass measurements. Finally, in silico toxicological screening of all metabolites was evaluated, and two metabolites were proposed to show a certain degree of lung or liver toxicity.

Nuevos antiagregantes plaquetarios en cardiopatía isquémica / New antiplatelet drugs in coronary artery disease

El doble tratamiento antiagregante con ácido acetilsalicílico y clopidogrel reduce considerablemente las complicaciones trombóticas de las fases aguda y crónica en la cardiopatía isquémica. Pese al buen cumplimiento terapéutico, un porcentaje no despreciable de pacientes continúa presentando episodios adversos. Por ello, nuevos compuestos farmacológicamente más favorables están ya disponibles clínicamente (como es el caso de prasugrel y ticagrelor) o en fases avanzadas de su desarrollo. La presente revisión tiene como objetivo principal la descripción de los nuevos fármacos antiagregantes, en especial prasugrel y ticagrelor (AU)

The dual antiplatelet therapy with acetylsalicylic acid and clopidogrel has been the mainstay of both acute and chronic phase coronary artery disease, reducing importantly the risk of adverse events. Despite a correct compliance, a non-negligible rate of adverse events still happens. New compounds, with improved properties, are now clinically available (such as prasugrel or ticagrelor) or under advanced development. The aim of the present review is the description of these new compounds, particularly prasugrel and ticagrelor (AU)

Interaction between thienopyridines and proton pump inhibitors.

Adenosin diphospat (ADP) plays a crucial role in thrombus formation. Therefore its inhibition can control excess platelet generation to prevent cardiovascular events in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). One of ADP's target receptors, P2Y12 has a limited tissue distribution and is therefore an attractive pharmacological target. Thienopyridines are class of drugs that specifically and irreversibly inhibit the P2Y12 receptor. Three generations exist and in most patients, they are administered in combination with aspirin. Because of possible gastro-intestinal toxicity, a proton pump inhibitor (PPI) is often concomitantly prescribed. However, several studies suspect an interaction between thienopyridines (in particular with clopidogrel) and PPIs which decreases the inhibition of platelet formation and thus enhances the risk for cardiac events. In this review, a concise overview of pharmacokinetic and pharmacodynamic properties of all thienopyridines is given and a critical discussion of the presumed interaction with PPIs is provided.

Prasugrel compared to clopidogrel in patients with acute coronary syndrome undergoing percutenous coronary intervention: a Spanish model-based cost-effectiveness analysis

OBJECTIVE: To assess the long-term cost-effectiveness of 12 months treatment of prasugrel compared to clopidogrel in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in the Spanish health care system. METHODS: A Markov state transition model was developed to estimate health outcomes, quality adjusted life years (QALYs), life years (LY), and costs over patients' lifetimes. Clinical inputs were based on an analysis of the TRITON-TIMI 38 clinical trial. Hospital readmissions captured during the trial in a sub-study of patients from eight countries (and subsequent re-hospitalisations modelled to accrue beyond the time horizon of the trial), were assigned to Spanish diagnosis-related group payment schedules to estimate hospitalisation costs. RESULTS: Mean total treatment costs were €11,427 and €10,910 for prasugrel and clopidogrel respectively. The mean cost of the study drug was €538 higher for prasugrel vs. clopidogrel, but rehospitalisation costs at 12 months were €79 lower for prasugrel due to reduced rates of revascularisation. Hospitalisation costs beyond 12 months were higher with prasugrel by €55, due to longer life expectancy (+0.071 LY and +0.054 QALYs) associated with the decreased nonfatal myocardial infarction rate in the prasugrel group. The incremental cost per life year and QALY gained with prasugrel was €7,198, and €9,489, respectively. CONCLUSION: Considering a willingness-to-pay threshold of €30,000/QALY gained in the Spanish setting, prasugrel represents a cost-effective option in comparison with clopidogrel among patients with ACS undergoing PCI

OBJETIVO: Evaluar a largo plazo el coste-efectividad de 12 meses de tratamiento con prasugrel frente a clopidogrel en pacientes con síndrome coronario agudo (SCA) sometidos a intervención coronaria percutánea (ICP) desde la perspectiva del sistema nacional de salud español. MÉTODOS: Se desarrolló un modelo de Markov de transición entre estados para estimar los resultados en salud, los años de vida ajustados por calidad (AVACs), los años de vida (AV) y los costes a lo largo de la vida de los pacientes. Los datos clínicos fueron obtenidos de un análisis del ensayo clínico TRITON-TIMI 38. Los reingresos hospitalarios registrados durante el ensayo en un subestudio de pacientes provenientes de ocho países, (y las subsiguientes rehospitalizaciones fueron modeladas para acumularse más alla del horizonte temporal del ensayo) fueron asignados a grupos relacionados con el diagnóstico españoles para estimar los costes de hospitalización. RESULTADOS: Los costes medios totales del tratamiento con prasugrel y clopidogrel fueron 11.427 € y 10.910 €, respectivamente. El coste medio del fármaco fue 538 € superior para prasugrel frente a clopidogrel, pero los costes de rehospitalización a los 12 meses fueron 79 € menores para prasugrel debido a la reducción en las tasas de revascularización. Los costes de hospitalización más allá de los 12 meses fueron 55 € superiores con prasugrel, debido a la mayor esperanza de vida (+0,071 AV y +0,054 AVACs) asociada a la reducción de la tasa de infartos de miocardio no mortales en el grupo de prasugrel. El coste-efectividad incremental por año de vida y AVAC ganado con prasugrel fue 7.198 € y 9.489 €, respectivamente. CONCLUSIÓN: Considerando el umbral de disponibilidad a pagar de 30.000 €/ AVAC para España, prasugrel representa una opción coste-efectiva en comparación con clopidogrel en pacientes con SCA sometidos a ICP

Tailored Thienopyridine therapy: no urgency for CYP2C19 genotyping.

Between 20% and 50% of cardiovascular patients treated with clopidogrel, an anti-P2Y12 drug, display high on-treatment platelet reactivity (HTPR) and are not adequately protected from major adverse cardiovascular events (MACE). Despite a minor influence of the CYP2C19*2 genetic variant on the pharmacodynamic response to clopidogrel (5% to 12%) and a limited or absent value for predicting stent thrombosis and MACE, this latter polymorphism is currently considered an important candidate to tailor anti-P2Y12 therapy during percutaneous coronary intervention. Seven studies have examined the value of CYP2C19*2 for predicting HTPR in comparison to a specific pharmacodynamic assay (VASP assay). Overall, the summarized sensitivity of the CYP2C19*2 genotype for predicting HTPR was 37.6% (95% CI: 32.2 to 43.3%), yielding a negative likelihood ratio of only 0.77 (95% CI: 0.68 to 0.86) which confirms its limited value as a routine clinical aid. A tailored anti-P2Y12 treatment strategy restricted to CYP2C19*2 carriers may be of some help, but this restrictive approach leaves out noncarriers with HTPR. As for platelet function testing, there is currently no convincing data to support that using CYP2C19*2 genotyping as a tailored anti-P2Y12 treatment would be an effective strategy and there is no urgency for CYP2C19 genotyping in clinical practice. Strategies incorporating genotyping, phenotyping, and clinical data in a stratified and sequential approach may be more promising.

The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day.

Our knowledge of the mechanisms of platelet-mediated thrombosis has increased dramatically over the last 40 years. This increased understanding has identified treatment strategies for acute coronary syndromes (ACS) by targeting key mediators of platelet activation and aggregation processes. Aspirin (acetylsalicylic acid) monotherapy improves patient outcomes by irreversibly inhibiting the cyclooxygenase (COX)-1 enzyme in the arachidonic acid pathway. The later-developed thienopyridines, prodrugs that irreversibly inhibit the P2Y(12) receptor, and therefore adenosine diphosphate (ADP) binding, further enhance platelet inhibition and patient outcomes. The thienopyridine clopidogrel has been the standard of care, but it is limited by variable response and treatment failure. A more potent thienopyridine, prasugrel, requires fewer hepatic metabolic steps for activation, and elicits significantly improved outcomes for patients with ACS. The increased potency of prasugrel is associated with an increase in Thrombolysis in Myocardial Infarction (TIMI)-defined major bleeding compared with clopidogrel. Ticagrelor represents a new chemical class of agents called the cyclopentyltriazolopyrimidines. It interacts reversibly with the platelet P2Y(12) receptor, and does not require metabolic bioactivation for activity. Data show a significant improvement in ischaemic outcomes, including mortality, for ticagrelor compared with clopidogrel, without an increase in overall major bleeding, although non-coronary artery bypass graft bleeding is increased. Glycoprotein IIb/IIIa targeted agents (abciximab, tirofiban and eptifibatide) are also used in ACS patients undergoing percutaneous coronary interventions. These inhibitors utilize a different mechanism of action by preventing fibrinogen-mediated platelet aggregation. Other therapeutic strategies for platelet inhibition are being evaluated, including the investigative protease-activated receptor (PAR)-1 and thromboxane A(2) antagonists. This review highlights the mechanisms of action of these agents, and the continuing evolution of ACS therapy.

Preparation of the thienopyridine derivatives loaded liposomes and study on the effect of compound-lipid interaction on release behavior.

The article describes characterization of two liposome formulations containing thienopyridine derivatives, namely TP-58 and TP-67. By preparing the liposomes, the concentration of the two compounds in ultrapure water was increased up to three orders of magnitude. After i.v. administration of the liposomes in rats, the initial compound plasma concentrations were enhanced more than fifty times relative to that after i.g. administration of the compound suspensions. It was found out that the release rate of TP-67 from the liposome both in vitro and in vivo was not significantly different from that of TP-58. TP-58 was more lipophilic than TP-67 according to partition coefficiency, and TP-67 had greater polarity than TP-58 based on polar surface area (PSA). With DSC, it was found out that the interaction magnitude between TP-67 and the lipid bilayer was not significantly different from that between TP-58 and the lipid bilayer, which accounted for the similarity of the two compounds in release rate both in vitro and in vivo. It indicated liposome can be used as a potential carrier for broading the application of TP-58 and TP-67. Interaction between the thienopyridine derivatives and the lipid bilayer is probably the decisive factor for compound release from the liposomes.

Genetics of ischemic stroke, stroke-related risk factors, stroke precursors and treatments.

Stroke remains a leading cause of death worldwide and the first cause of disability in the western world. Ischemic stroke (IS) accounts for almost 80% of the total cases of strokes and is a complex and multifactorial disease caused by the combination of vascular risk factors, environment and genetic factors. Investigations of the genetics of atherosclerosis and IS has greatly enhanced our knowledge of this complex multifactorial disease. In this article we sought to review common single-gene disorders relevant to IS, summarize candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors and subclinical phenotypes, and to briefly discuss pharmacogenetics related to stroke treatments. Genetics of IS is, in fact, one of the most promising research frontiers and genetic testing may be helpful for novel drug discoveries as well as for appropriate drug and dose selection for treatment of patients with cerebrovascular disease.

Antiplatelet drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

The article describes the mechanisms of action, pharmacokinetics, and pharmacodynamics of aspirin, dipyridamole, cilostazol, the thienopyridines, and the glycoprotein IIb/IIIa antagonists. The relationships among dose, efficacy, and safety are discussed along with a mechanistic overview of results of randomized clinical trials. The article does not provide specific management recommendations but highlights important practical aspects of antiplatelet therapy, including optimal dosing, the variable balance between benefits and risks when antiplatelet therapies are used alone or in combination with other antiplatelet drugs in different clinical settings, and the implications of persistently high platelet reactivity despite such treatment.

Enfermedad aterotrombótica coronaria: avances en el tratamiento antiplaquetario / Coronary atherothrombotic disease: progress in antiplatelet therapy

La plaqueta ha asumido un papel preponderante en la medicina cardiovascular gracias a la comprensión del síndrome coronario agudo (SCA) como un proceso aterotrombótico. Esto ha establecido el uso generalizado de agentes antiplaquetarios, como la aspirina, las tienopiridinas y los antagonistas de los receptores de la glucoproteína IIb/IIIa, en la prevención de las enfermedades isquémicas coronarias. Sin embargo, hay evidencias recientes de que no todos los pacientes reciben el tratamiento antiplaquetario adecuado, ya sea por el fenómeno de la «resistencia» o «respuesta variable» al fármaco o por un aumento en el riesgo de sangrado. Es más, la falta de eficacia de la combinación aspirina-clopidogrel en la prevención primaria ha cuestionado el concepto de «a mayor inhibición, mayor eficacia». Actualmente, los esfuerzos se centran en la mejora de los tratamientos antiplaquetarios en uso a fin de mejorar su efectividad y su seguridad. Se están desarrollando antagonistas alternativos de los receptores del ADP (prasugrel, AZD6140 y cangrelor) y de la trombina (E555 y SCH530348) que podrían ofrecer más inhibición de las plaquetas, más rápida y constante. Asimismo, el avance en el conocimiento de la estructura de la plaqueta y los mecanismos implicados en la formación del trombo puede dar lugar al descubrimiento de nuevas dianas terapéuticas. Este artículo revisa el papel fisiopatológico de las plaquetas en el proceso aterotrombótico, evalúa lo más actual del arsenal antiplaquetario actualmente en uso y comenta nuevas aproximaciones terapéuticas (AU)

Platelets are now regarded as playing a dominant role in cardiovascular medicine since our recent understanding of acute coronary syndrome as an atherothrombotic process. This development has led to the widespread use of antiplatelet agents, such as aspirin, thienopyridines and glycoprotein-IIb/IIIa receptor blockers, for the prevention of ischemic heart disease. Nevertheless, recent evidence suggests that not all patients receive appropriate antiplatelet therapy because there may be resistance or a variable response to the drug used or because of an increased risk of hemorrhage. Moreover, the reported lack of efficacy of the combination of clopidogrel and aspirin when used for primary prevention has raised concerns about the general concept that greater inhibition implies greater efficacy. At present, research efforts are focused on improving current antiplatelet treatment with the aim of increasing efficacy and safety. Alternative ADP-receptor antagonists (e.g., prasugrel, cangrelor and AZD6140) and thrombin-receptor antagonists (e.g., E5555 and SCH 530348) are being developed. They may provide faster, more potent and more stable platelet inhibition. In addition, new insights into platelet structure and into the mechanisms underlying thrombus formation could lead to the discovery of new therapeutic targets. This article reviews what is known about the pathophysiological role of platelets in the atherothrombotic process, considers the current state of the art in antiplatelet therapy, and provides a commentary on new therapeutic approaches (AU)