The P2Y12 Receptor Antagonist Selatogrel Dissolves Preformed Platelet Thrombi In Vivo

Crescence, Lydie; Kramberg, Markus; Baumann, Martine; Rey, Markus; Roux, Sébastiên; Panicot‐Dubois, Laurence; Dubois, Christophe; Riederer, Markus A.

doi:10.3390/jcm10225349

Cited by 6 publications

(5 citation statements)

References 37 publications

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“…It appears that the combination of selatogrel with ticagrelor might produce the most pronounced platelet inhibitory activity, while a time gap between selatogrel administration and prasugrel/clopidogrel intake needs to be implemented so that the pharmacodynamic effects of the latter remains intact [ 145 ]. Selatogrel may also possess a thrombolytic role as recently proposed by Cresence et al, who noted dissolution of the occlusive part of preformed thrombi, with the remaining part potentially serving as hemostatic seal at the site of vessel injury [ 146 ]. Future randomized controlled trials with major clinical endpoints may shed more light in the potential of this novel molecule in acute atherothrombotic scenarios.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Factors Associated with Platelet Activation-Recent Pharmaceutical Approaches

Theofilis

Sagris

Oikonomou

et al. 2022

IJMS

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Platelets are at the forefront of human health and disease following the advances in their research presented in past decades. Platelet activation, their most crucial function, although beneficial in the case of vascular injury, may represent the initial step for thrombotic complications characterizing various pathologic states, primarily atherosclerotic cardiovascular diseases. In this review, we initially summarize the structural and functional characteristics of platelets. Next, we focus on the process of platelet activation and its associated factors, indicating the potential molecular mechanisms involving inflammation, endothelial dysfunction, and miRs. Finally, an overview of the available antiplatelet agents is being portrayed, together with agents possessing off-set platelet-inhibitory actions, while an extensive presentation of drugs under investigation is being given.

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Section: Therapeutic Approachesmentioning

confidence: 99%

Factors Associated with Platelet Activation-Recent Pharmaceutical Approaches

Theofilis

Sagris

Oikonomou

et al. 2022

IJMS

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“…That P2Y 12 receptors have a thrombus-stabilizing role was also concluded from in vivo studies with Apoe -/- mice, where plaque-induced thrombus formation and stability were impaired upon receptor blockage [ 66 ]. Additionally, in mouse models, application of a reversible P2Y 12 antagonist was found to dissolve the preformed platelet thrombi [ 67 ]. Together these findings point to major roles of the two platelet ADP receptors in stable arterial thrombus formation.…”

Section: Reversible Integrin Activation and Thrombus Instabilitymentioning

confidence: 99%

Reversible Platelet Integrin αIIbβ3 Activation and Thrombus Instability

Zou

Swieringa

Laat

et al. 2022

IJMS

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Integrin αIIbβ3 activation is essential for platelet aggregation and, accordingly, for hemostasis and arterial thrombosis. The αIIbβ3 integrin is highly expressed on platelets and requires an activation step for binding to fibrinogen, fibrin or von Willebrand factor (VWF). A current model assumes that the process of integrin activation relies on actomyosin force-dependent molecular changes from a bent-closed and extended-closed to an extended-open conformation. In this paper we review the pathways that point to a functional reversibility of platelet αIIbβ3 activation and transient aggregation. Furthermore, we refer to mouse models indicating that genetic defects that lead to reversible platelet aggregation can also cause instable thrombus formation. We discuss the platelet agonists and signaling pathways that lead to a transient binding of ligands to integrin αIIbβ3. Our analysis points to the (autocrine) ADP P2Y1 and P2Y12 receptor signaling via phosphoinositide 3-kinases and Akt as principal pathways linked to reversible integrin activation. Downstream signaling events by protein kinase C, CalDAG-GEFI and Rap1b have not been linked to transient integrin activation. Insight into the functional reversibility of integrin activation pathways will help to better understand the effects of antiplatelet agents.

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“…Preclinical experiments demonstrated the potent anti-thrombotic properties of selatogrel by preventing and dissolving platelet thrombi without disrupting hemostatic seals, while the off-target activity of clopidogrel and ticagrelor destabilized mural platelet thrombi [ 32 ]. Subcutaneous application rapidly inhibited ongoing thrombosis in guinea pigs and mice, even normalizing blood flow in a thrombosis model [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Mind the Gap: Model-Based Switching from Selatogrel to Maintenance Therapy with Oral P2Y12 Receptor Antagonists

Hsin,

Dingemanse,

Henrich

et al. 2023

Biomolecules

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Background: The P2Y12 receptor antagonist selatogrel is being developed for subcutaneous self-administration with a ready-to-use autoinjector at the onset of acute myocardial infarction (AMI) symptoms. The unique pharmacological profile of selatogrel (fast, potent, and short-acting) can bridge the time gap between the onset of AMI and first medical care. A clinical Phase 1 study showed a time-dependent pharmacodynamic interaction between selatogrel and loading doses of clopidogrel and prasugrel. As treatment switching is a common clinical practice, the assessment of subsequent switching from a clopidogrel loading dose to the first maintenance dose of oral P2Y12 receptor antagonists is highly relevant. Objectives: Model-based predictions of inhibition of platelet aggregation (IPA) for the drugs triggering pharmacodynamic interactions were to be derived to support clinical guidance on the transition from selatogrel to oral P2Y12 receptor antagonists. Methods: Scenarios with selatogrel 16 mg administration or placebo followed by a clopidogrel loading dose and, in turn, prasugrel or ticagrelor maintenance doses at different times of administration were studied. Population pharmacokinetic/pharmacodynamic modeling and simulations of different treatment scenarios were used to derive quantitative estimates for IPA over time. Results: Following selatogrel/placebo and a clopidogrel loading dose, maintenance treatment with ticagrelor or a prasugrel loading dose followed by maintenance treatment quickly achieved sustained IPA levels above 80%. Prior to maintenance treatment, a short time span from 18 to 24 h was identified where IPA levels were predicted to be lower with selatogrel than with placebo if clopidogrel was administered 12 h after selatogrel or placebo. Predicted IPA levels reached with placebo alone and a clopidogrel loading dose at 4 h were consistently lower than with selatogrel administration, followed by a clopidogrel loading dose at 12 h. If a clopidogrel loading dose is administered at 12 h, selatogrel maintains higher IPA levels up to 16 h. IPA levels are subsequently lower than on the placebo until the administration of the first maintenance dose. Conclusions: Model-based predictions informed the transition from selatogrel subcutaneous administration to oral P2Y12 therapy. The application of modeling techniques illustrates the value of employing pharmacokinetic and pharmacodynamic modeling for the simulation of various clinical scenarios of switching therapies.

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The P2Y12 Receptor Antagonist Selatogrel Dissolves Preformed Platelet Thrombi In Vivo

Cited by 6 publications

References 37 publications

Factors Associated with Platelet Activation-Recent Pharmaceutical Approaches

Factors Associated with Platelet Activation-Recent Pharmaceutical Approaches

Reversible Platelet Integrin αIIbβ3 Activation and Thrombus Instability

Mind the Gap: Model-Based Switching from Selatogrel to Maintenance Therapy with Oral P2Y12 Receptor Antagonists

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