Adenosine receptor agonists deepen the inhibition of platelet aggregation by P2Y12 antagonists

Boncler, Magdalena; Wzorek, Joanna; Wolska, Nina; Polak, Dawid; Watała, Cezary; Różalski, Marcin

doi:10.1016/j.vph.2018.11.005

Cited by 23 publications

(43 citation statements)

References 46 publications

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“…What is important is the effect was specific, as the examined AR agonists were not cytotoxic for the cells and their action was much more pronounced in individuals with poor response to P2Y 12 inhibitors. In a certain sense, this study supports and complements our recent in vitro work, where the anti-aggregatory activity of other AR agonists was examined in the absence or presence of the P2Y 12 antagonists given above [18].…”

Section: Discussionsupporting

confidence: 85%

“…In addition, the AR agonist which did not display antiaggregatory properties was analysed further at the highest used concentration: 100 µM. Cangrelor and prasugrel, being strong P2Y 12 inhibitors, were used at the IC 50 values, which were previously reported [18].…”

Section: Discussionmentioning

confidence: 99%

“…AR agonists were used in a combination with two P2Y 12 receptor antagonists (one AR agonist + one P2Y 12 antagonist in each combination): cangrelor and prasugrel metabolite R-138727 (PM). Each compound was used in its IC 50 , with the values taken from our previous work [18]: NECA 0.5 µM, regadenoson 1.2 µM, cangrelor 17 nM, and PM 1.3 µM. In the case of LUF5835, it was not possible to establish an inhibition curve or an IC 50 value; therefore, a concentration of 100 µM was used.…”

Section: Combined Effect Of Ar Agonists and P2y 12 Inhibitors On Platmentioning

confidence: 99%

“…Unfortunately, such treatment is still beset by the problem of resistance, especially among patients with type 2 diabetes, i.e., a group at higher risk of thromboembolic events [15][16][17]. We recently proposed a novel approach based on the simultaneous application of two anti-platelet agents, a P2Y 12 antagonist and an AR agonist, which was found to deepen the action of P2Y 12 antagonist [18].The aim of this study is to further explore the potential of combined anti-platelet therapy consisting of simultaneous P2Y 12 inhibition and adenosine receptor agonization. The lowered dosage of P2Y 12 inhibitors could potentially reduce side-effects (e.g., excessive bleeding), while the addition of AR agonization would provide adequate anti-platelet effect, and therefore excessive clot formation prevention.…”

mentioning

confidence: 99%

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confidence: 99%

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Adenosine Receptor Agonists Exhibit Anti-Platelet Effects and the Potential to Overcome Resistance to P2Y12 Receptor Antagonists

et al. 2019

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Large inter-individual variation in platelet response to endogenous agonists and pharmacological agents, including resistance to antiplatelet therapy, prompts a search for novel platelet inhibitors and development new antithrombotic strategies. The present in vitro study evaluates the beneficial effects of three adenosine receptor (AR) agonists (regadenoson, LUF 5835 and NECA), different in terms of their selectivity for platelet adenosine receptors, when used alone and in combination with P2Y 12 inhibitors, such as cangrelor or prasugrel metabolite. The anti-platelet effects of AR agonists were evaluated in healthy subjects (in the whole group and after stratification of individuals into high-and low-responders to P2Y 12 inhibitors), using whole blood techniques, under flow (thrombus formation) and static conditions (study of platelet activation and aggregation). Compared to P2Y 12 antagonists, AR agonists were much less or not effective under static conditions, but demonstrated similar antiplatelet activity in flow. In most cases, AR agonists significantly enhanced the anti-platelet effect of P2Y 12 antagonists, despite possessing different selectivity profiles and antiplatelet activities. Importantly, their inhibitory effects in combination with P2Y 12 antagonists were similar in high-and low-responders to P2Y 12 inhibitors. In conclusion, a combination of anti-platelet agents acting via the P1 and P2 purinergic receptors represents a promising alternative to existing antithrombotic therapy.Molecules 2020, 25, 130 2 of 17 ADP is one of the key mediators of both physiological haemostasis and thrombosis, being not only a direct agonist of platelets, but also an important factor released from platelet intracellular structures, enhancing the platelet response initially induced by other activators. Platelets have two ADP receptors on their surface: the P2Y 1 receptor initiates platelet aggregation, while the P2Y 12 receptor enhances this process, eventually leading to the formation of a clot. Due to this fact, the P2Y 12 receptor is the main therapeutic target in anti-platelet therapy targeted at the ADP-dependent activation pathway [5]. Generally, the most commonly used clinically approved P2Y 12 inhibitors include the thienopyridine-class inhibitors (ticlopidine, clopidogrel and prasugrel), the ATP analogue cangrelor, and the cyclo-pentyl-triazolo-pyrimidine derivative ticagrelor [3,5]. Thienopyridines are prodrugs: their short-lived active metabolites irreversibly inactivate the receptor and consequently inhibit ADP-induced platelet activation. Cangrelor is the first (recently approved) intravenous P2Y 12 receptor inhibitor that reversibly and non-competitively blocks ADP signalling [6].Adenosine is an important purine metabolite, serving not only as a component of nucleic acids and ATP, the most important energy carrier in the cell, but also as a signalling molecule regulating many cell processes [7,8]. Adenosine receptors (AR) are a subfamily of highly conserved G protein-coupled receptors located in the membr...

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Combined Effect Of Ar Agonists and P2y 12 Inhibitors On Platmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Adenosine Receptor Agonists Exhibit Anti-Platelet Effects and the Potential to Overcome Resistance to P2Y12 Receptor Antagonists

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Adenosine and the Cardiovascular System

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Grossfeld

Kasselman

et al. 2019

Am J Cardiovasc Drugs

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Interactions of fentanyl with blood platelets and plasma proteins: platelet sensitivity to prasugrel metabolite is not affected by fentanyl under in vitro conditions

et al. 2023

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Background Clinical trials indicate that fentanyl, like morphine, may impair intestinal absorption and thus decrease the efficacy of oral P2Y12 inhibitors, such as clopidogrel, ticagrelor, and prasugrel. However, the ability of fentanyl to directly negate or reduce the inhibitory effect of P2Y12 receptor antagonists on platelet function has not been established. A series of in vitro experiments was performed to investigate the ability of fentanyl to activate platelets, potentiate platelet response to ADP, and/or diminish platelet sensitivity to prasugrel metabolite (R-138727) in agonist-stimulated platelets. The selectivity and specificity of fentanyl toward major carrier proteins has been also studied. Methods Blood was obtained from healthy volunteers (19 women and 12 men; mean age 40 ± 13 years). Platelet function was measured in whole blood, platelet-rich plasma and in suspensions of isolated platelets by flow cytometry, impedance and optical aggregometry. Surface plasmon resonance and molecular docking were employed to determine the binding kinetics of fentanyl to human albumin, α1-acid glycoprotein, apolipoprotein A-1 and apolipoprotein B-100. Results When applied at therapeutic and supratherapeutic concentrations under various experimental conditions, fentanyl had no potential to stimulate platelet activation and aggregation, or potentiate platelet response to ADP, nor did it affect platelet susceptibility to prasugrel metabolite in ADP-stimulated platelets. In addition, fentanyl was found to interact with all the examined carrier proteins with dissociation constants in the order of 10–4 to 10–9 M. Conclusions It does not seem that the delayed platelet responsiveness to oral P2Y12 inhibitors, such as prasugrel, in patients undergoing percutaneous coronary intervention, results from direct interactions between fentanyl and blood platelets. Apolipoproteins, similarly to albumin and α1-acid glycoprotein, appear to be important carriers of fentanyl in blood.

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Adenosine receptor agonists deepen the inhibition of platelet aggregation by P2Y12 antagonists

Cited by 23 publications

References 46 publications

Adenosine Receptor Agonists Exhibit Anti-Platelet Effects and the Potential to Overcome Resistance to P2Y12 Receptor Antagonists

Adenosine Receptor Agonists Exhibit Anti-Platelet Effects and the Potential to Overcome Resistance to P2Y12 Receptor Antagonists

Adenosine and the Cardiovascular System

Interactions of fentanyl with blood platelets and plasma proteins: platelet sensitivity to prasugrel metabolite is not affected by fentanyl under in vitro conditions

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