Cibles des médicaments antithrombotiques

Pour la quasi-totalité des classes thérapeutiques antithrombotiques actuellement utilisées et à venir, le ciblage a été initialement la conséquence d’une observation et non pas le fruit d’une recherche méthodique scientifique. Une fois la preuve de l’efficacité démontrée, le but du développement pharmaceutique a été de découvrir des familles moléculaires qui améliorent l’efficacité et les relations cinétique/dynamique. Les rares cas de développement d’une stratégie contre une cible spécifique, identifiée à partir des connaissances des mécanismes fondamentaux de la thrombogenèse, n’ont pas été des succès. La nature paraît avoir déjà exploité toutes les cibles efficaces et il semble qu’il n’est possible que de la copier en essayant de l’améliorer par quelques détails pharmacocinétiques ou galéniques attractifs. Quoiqu’il en soit, le développement de nombreuses formes moléculaires dirigées contre plusieurs cibles a lieu et la mise à disposition de molécules spécifiques des différentes cibles devrait modifier notre prise en charge des états thrombotiques chez les patients : nous allons passer d’une ère où nous cherchions à utiliser au mieux les rares thérapeutiques dont nous disposions à une ère où nous aurons à déterminer, pour chaque situation thrombotique, la meilleure cible à inhiber et le meilleur degré d’inhibition à atteindre.New antithrombotic agents are being developed not only to improve efficacy, but also to increase safety in comparison with widely used conventional agents such as the oral anticoagulants. New anticoagulant, antiplatelet, and profibrinolytic compounds are currently under study in drug development programs, and most of those in phase II or III of development are derived from the observation of natural phenomena and merely mimic processes developed by mammalians, including humans, to avoid thrombosis, or by blood-sucking insects or animals to prevent coagulation of the blood their are feeding on. By contrast, drug candidates identified by means of rigorous research and designed to target new pathways and achieve direct and specific inhibition of factors that are presumed to play an important role in thrombogenesis have generally failed to show any benefit and sometimes even induce deleterious effects. The clinical development of new drugs, even those mimicking natural phenomena, improves our knowledge of the pathogenesis of thrombosis and sheds light, retrospectively, on previous conceptual errors. The improvement in our basic knowledge and the development of new types of drugs suggest that, in contrast to the current antithrombotic compounds that are used in a broad range of clinical settings, use of new drugs should be restricted to specific situations in which their mechanisms of action are predicted to deliver the highest medical benefit. A major obstacle resides in the fact that current drug development programs are still required to comply with long obsolete guidelines based on the characteristics of first-generation antithrombotic agents, and that do not take into account the specific mechanisms of action of new drugs. This situation should change, however, and new antithrombotic drugs should soon be able to benefit from adapted development programs that will make it possible to determine their optimal risk-benefit ratio

Eptifibatide provides additional platelet inhibition in Non–ST-Elevation myocardial infarction patients already treated with aspirin and clopidogrel Results of the platelet activity extinction in Non–Q-Wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study

AbstractObjectivesThe present study hypothesis was that eptifibatide offered further antiplatelet efficacy above clopidogrel in non–ST-elevation myocardial infarction (NSTEMI) patients before an expeditive coronary intervention.BackgroundAlthough thienopyridines and glycoprotein (GP) IIb/IIIa antagonists are often co-prescribed in the context of NSTEMI, the antiplatelet interaction of these agents is poorly described and the superiority of GP IIb/IIIa antagonists above thienopyridine treatment alone is not clear.MethodsThirty-two NSTEMI patients treated with aspirin and enoxaparin were studied using flow cytometry to define parameters of platelet activation with a panel of agonists before clopidogrel, after clopidogrel, and during an eptifibatide infusion following the clopidogrel load.ResultsAfter platelet activation with adenosine diphosphate, thrombin receptor-activating peptide, or U46-619, relative reductions in conformationally activated GP IIb/IIIa receptor expression (evaluated with PAC-1) of 48%, 43%, and 33%, respectively (all p < 0.0001), were seen with clopidogrel, but further 80%, 78%, and 72% (all p < 0.0001) reductions were seen with eptifibatide. With the same agonists, fibrinogen binding was significantly reduced after clopidogrel by 70%, 64%, and 81% (all p < 0.0001) and again further reduced with eptifibatide by 90%, 95%, and 69% (all p < 0.0001). The total number of GP IIb/IIIa receptors (measured as P2 expression) and P-selectin expression fell after clopidogrel, after ex vivo stimulation with the same agonists; however, both parameters increased slightly during the eptifibatide infusion.ConclusionsThe activated GP IIb/IIIa expression and fibrinogen binding findings indicate that eptifibatide provides significant potent antiplatelet activity above aspirin and clopidogrel, suggesting additive immediate protection in the treatment of NSTEMI. The P2 and P-selectin findings suggest the possibility of a partial agonist and/or pro-inflammatory effect

MOL#8268 1 Title Page. The natural mutation encoding a C-terminus truncated 5-HT 2B receptor is a gain of proliferative functions

Number of tables, 1 Number of references, 31 Number of words in the abstract, 230 Number of words in the Introduction, 744 Number of words in the Discussion. 1172 List of non-standard abbreviations receptor was identified in one patient diagnosed with pulmonary hypertension after intake of the anorexigen dexfenfluramine. Although reported to generate a lack of function, this C-terminus truncated 5-HT 2B receptor should somehow affect transduction pathways relevant to pulmonary hypertension. In our study, we investigated putative modifications in transduction of the R393X mutated 5-HT 2B receptor. In stably transfected cells, we confirmed the loss of IP 3 stimulation due to the G αq uncoupling, despite conserved ligand affinity between the normal and mutated receptors. We also observed a partial loss of nitric oxide synthase stimulation. However, the truncated R393X receptor presented (i) a strong gain of efficacy in cell proliferation as assessed by mitogen-activated protein kinase activity and thymidine incorporation, (ii) a preferential coupling to G α13 as shown by blocking antiserum, and (iii) an apparent lack of internalization upon agonist stimulation as observed by confocal microscopy. This work demonstrates that, in the 5-HT 2B receptor, the C-terminus including the palmitoylation and phosphorylation sites is absolutely required for proper transduction and internalization. For the first time, we show that the lack of C-terminus can generate a switch of coupling to G α13 , a reduced NO synthase activation and an increase in cell proliferation. All these modifications are relevant in pathophysiological vasoconstriction. MOL#8268 4 Introduction

A Randomized Comparison of High Clopidogrel Loading Doses in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes The ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) Trial

ObjectivesWe sought to compare the antiplatelet effects of three clopidogrel loading doses (LDs).BackgroundAdministration of a 300-mg clopidogrel LD is beneficial in situations requiring rapid platelet inhibition. Whether higher LDs can provide further benefits remains unknown.MethodsPatients (n = 103) with non–ST-segment elevation acute coronary syndromes were randomized to receive a 300-mg, 600-mg, or 900-mg clopidogrel LD, given on top of other standard therapy (including acetylsalicylic acid). The main outcome measure was inhibition of adenosine diphosphate-induced inhibition of platelet aggregation (IPA); inhibition of platelet activation, inflammatory markers, troponin I release, and major adverse cardiac events also were evaluated; all measures were blindly evaluated.ResultsCompared with the 300-mg LD, greater doses were associated with significantly greater platelet inhibition, with dose-effect relationships observed for onset of action, maximal plateau, 24-h areas under the curves of IPA, and rates of low IPA (<10% at 6 h), using 20 μmol/l major adverse cardiac events. A significant dose-response was also observed for the vasodilator-stimulated phosphoprotein index, a measure of P2Y12receptor inhibition. Similar but nonsignificant trends were observed for troponin release and major adverse cardiac events. Bleeding rates were similar in each group.ConclusionsIn low-to-moderate risk patients with non–ST-elevation acute coronary syndromes, clopidogrel LDs >300 mg provide a faster onset of action, a higher IPA plateau, and greater reductions in platelet activation during the first 24 h. A 900-mg LD may induce a greater antiplatelet effect than 600 mg, when compared with the standard 300-mg regimen. These findings require further clinical confirmation

Educational Impact on Apixaban Adherence in Atrial Fibrillation (the AEGEAN STUDY): A Randomized Clinical Trial

IntroductionAdherence to non-vitamin-K oral anticoagulants (NOACs) may be lower than to vitamin K antagonists because NOACs do not require routine monitoring.ObjectiveWe assessed the impact of an educational program on adherence and persistence with apixaban in patients with non-valvular atrial fibrillation (NVAF).MethodsPatients with NVAF eligible for NOACs with one or more stroke risk factor (prior stroke/transient ischemic attack, age ≥ 75 years, hypertension, diabetes, or symptomatic heart failure) were randomized (1:1) to standard of care (SOC) or SOC with additional educational (information booklet, reminder tools, virtual clinic access). The primary outcome was adherence to apixaban (2.5 or 5 mg twice daily) at 24 weeks. Patients receiving the educational program were re-randomized (1:1) to continue the program for 24 further weeks or to switch to secondary SOC. Implementation adherence and persistence were reassessed at 48 weeks.ResultsIn total, 1162 patients were randomized (SOC, 583; educational program, 579). Mean implementation adherence ± standard deviation (SD) at 24 weeks was 91.6% ± 17.1 for SOC and 91.9% ± 16.1 for the educational program arm; results did not differ significantly between groups at any time-point. At 48 weeks, implementation adherence was 90.4% ± 18.0, 90.1% ± 18.6, and 89.3% ± 18.1 for continued educational program, SOC, and secondary SOC, respectively; and corresponding persistence was 86.1% (95% confidence interval [CI] 81.3-89.7), 85.2% (95% CI 81.5-88.2), and 87.8% (95% CI 83.4-91.1). Serious adverse events were similar across groups.ConclusionHigh implementation adherence and persistence with apixaban were observed in patients with NVAF receiving apixaban. The educational program did not show additional benefits.Clinical trial registrationThis study is registered at ClinicalTrials.gov [NCT01884350]

Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras.

von Willebrand factor (vWF) is essential for the induction of occlusive thrombosis in stenosed and injured pig arteries and for normal hemostasis. To separate the relative contribution of plasma and platelet vWF to arterial thrombosis, we produced chimeric normal and von Willebrand disease pigs by crossed bone marrow transplantation; von Willebrand disease (vWD) pigs were engrafted with normal pig bone marrow and normal pigs were engrafted with vWD bone marrow. Thrombosis developed in the chimeric normal pigs that showed normal levels of plasma vWF and an absence of platelet vWF; but no thrombosis occurred in the chimeric vWD pigs that demonstrated normal platelet vWF and an absence of plasma vWF. The ear bleeding times of the chimeric pigs were partially corrected by endogenous plasma vWF but not by platelet vWF. Our animal model demonstrated that vWF in the plasma compartment is essential for the development of arterial thrombosis and that it also contributes to the maintenance of bleeding time and hemostasis

Contribution à l'étude du Lepidium Meyenii (la maca)

NANCY1-SCD Pharmacie-Odontologie (543952101) / SudocNANCY1-Bib. numérique (543959902) / SudocSudocFranceF