Pharmacodynamic properties of antiplatelet agents: current knowledge and future perspectives

Kalantzi, Kallirroi I; Tsoumani, Maria; Goudevenos, Ioannis; Tselepis, Alexandros D.

doi:10.1586/ecp.12.19

Cited by 48 publications

(29 citation statements)

References 129 publications

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“…P2Y 12 -R is also coupled to G q , which through phospholipase C activation increases intracellular Ca 2+ needed for platelet activation. 19 Both inhibition of AC activity and activation of phospholipase C are known to decrease the sensitivity of CD to AVP. 2 Hence, we hypothesized that if expressed in the kidney, P2Y 12 -R may play a role in renal handling of water and in pathophysiology of NDI.…”

mentioning

confidence: 99%

P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus

Zhang¹,

Peti‐Peterdi

Müller

et al. 2015

Journal of the American Society of Nephrology

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P2Y12 receptor (P2Y12-R) signaling is mediated through Gi, ultimately reducing cellular cAMP levels. Because cAMP is a central modulator of arginine vasopressin (AVP)-induced water transport in the renal collecting duct (CD), we hypothesized that if expressed in the CD, P2Y12-R may play a role in renal handling of water in health and in nephrogenic diabetes insipidus. We found P2Y12-R mRNA expression in rat kidney, and immunolocalized its protein and aquaporin-2 (AQP2) in CD principal cells. Administration of clopidogrel bisulfate, an irreversible inhibitor of P2Y12-R, significantly increased urine concentration and AQP2 protein in the kidneys of Sprague-Dawley rats. Notably, clopidogrel did not alter urine concentration in Brattleboro rats that lack AVP. Clopidogrel administration also significantly ameliorated lithium-induced polyuria, improved urine concentrating ability and AQP2 protein abundance, and reversed the lithium-induced increase in free-water excretion, without decreasing blood or kidney tissue lithium levels. Clopidogrel administration also augmented the lithium-induced increase in urinary AVP excretion and suppressed the lithium-induced increase in urinary nitrates/nitrites (nitric oxide production) and 8-isoprostane (oxidative stress). Furthermore, selective blockade of P2Y12-R by the reversible antagonist PSB-0739 in primary cultures of rat inner medullary CD cells potentiated the expression of AQP2 and AQP3 mRNA, and cAMP production induced by dDAVP (desmopressin). In conclusion, pharmacologic blockade of renal P2Y12-R increases urinary concentrating ability by augmenting the effect of AVP on the kidney and ameliorates lithium-induced NDI by potentiating the action of AVP on the CD. This strategy may offer a novel and effective therapy for lithium-induced NDI.

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mentioning

confidence: 99%

P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus

Zhang¹,

Peti‐Peterdi

Müller

et al. 2015

Journal of the American Society of Nephrology

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“…aspirin (ASA), pentoxyfilline and dipyridamole; and anti-coagulants, such as heparin and warfarin; with the aim of inhibiting both platelet activation (PA) and subsequent zymogen coagulation pathways driving thrombotic events [6]. However, despite current anti-thrombotic strategy, the occurrence of post-implant thrombosis persists [7], raising concerns as to the actual efficacy of present drug regimens.…”

Section: Introductionmentioning

confidence: 99%

Microfludic platforms for the evaluation of anti-platelet agent efficacy under hyper-shear conditions associated with ventricular assist devices

Dimasi

Rasponi

Consolo

et al. 2017

Medical Engineering & Physics

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Thrombus formation is a major adverse event affecting patients implanted with ventricular assist devices (VADs). Despite anti-thrombotic drug administration, thrombotic events remain frequent within the first year post-implantation. Platelet activation (PA) is an essential process underling thrombotic adverse events in VAD systems. Indeed, abnormal shear forces, correlating with specific flow trajectories of VADs, are strong agonists mediating PA. To date, the ability to determine efficacy of anti-platelet (AP) agents under shear stress conditions is limited. Here, we present a novel microfluidic platform designed to replicate shear stress patterns of a clinical VAD, and use it to compare the efficacy of two AP agents in vitro. Gel-filtered platelets were incubated with i) acetylsalicylic acid (ASA) and ii) ticagrelor, at two different concentrations (ASA: 125 and 250μM; ticagrelor: 250 and 500nM) and were circulated in the VAD-emulating microfluidic platform using a peristaltic pump. GFP were collected after 4 and 52 repetitions of exposure to the VAD shear pattern and tested for shear-mediated PA. ASA significantly inhibited PA only at 2-fold higher concentration (250 μM) than therapeutic dose (125 μM). The effect of ticagrelor was not dependent on drug concentration, and did not show significant inhibition with respect to untreated control. This study demonstrates the potential use of microfluidic platforms as means of testing platelet responsiveness and AP drug efficacy under complex and realistic VAD-like shear stress conditions.

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“…The currently available antiplatelet agents target key steps leading to platelet activation, including TxA 2 synthesis, ADPmediated signaling, and integrin-receptor α IIb β 3 -mediated platelet aggregation [5]. Aspirin, an irreversible inhibitor of cyclooxygonase-1 (COX-1), reduces the production of TxA 2 from arachidonic acid thus leading to reduced TxA 2 -dependent platelet aggregation.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the prodrug clopidogrel which irreversibly antagonizes the P2Y 12 is used worldwide. Dual antiplatelet therapy (DAPT), typically with clopidogrel and aspirin, is commonly used for the prevention of cardiovascular events [5]. More recently, ticagrelor, which reversibly and directly antagonizes P2Y 12 receptor, is being used as an alternative to clopidogrel due to its better efficacy profile.…”

Section: Introductionmentioning

confidence: 99%

Dynamic platelet adhesion in patients with an acute coronary syndrome: The effect of antiplatelet therapy

et al. 2016

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Platelet adhesion and aggregation are key functions leading to thrombus formation. The effect of aspirin, clopidogrel, and ticagrelor on platelet aggregation has been well established, however, there is limited data on the effect of these drugs on platelet adhesion. We therefore evaluated the effect of these drugs on platelet adhesion in acute coronary syndrome (ACS) patients. Citrated blood was collected from 50 ACS patients loaded with 325 mg of aspirin (baseline) and at 5 days after the administration of aspirin 100 mg/day and clopidogrel (600 mg loading dose, 75 mg/day) (n = 26) or ticagrelor (180 mg loading dose, 90 mg × 2/day) (n = 24). High on-treatment platelet reactivity (HTPR) to clopidogrel was estimated by vasodilator stimulated phosphoprotein (VASP) phosphorylation assay. Platelet adhesion to collagen was studied for 6 min under high shear stress and was evaluated using the time to platelet recruitment (TPR), the perimeter and average area of each adherent object, number of adherent objects, and the total percent of surface coverage (SC%). Six ACS patients exhibited HTPR to clopidogrel and excluded from the platelet adhesion assays. TPR and SC% values were similar among patient groups at baseline and controls. However, all other adhesion parameters were different in ACS patients, indicating the formation of more aggregates in regard to controls. At 5 days post-treatment with either clopidogrel or ticagrelor, the TPR values were increased and the SC% values were reduced to a similar extent compared with baseline. However, significant differences were observed in the ticagrelor group in the perimeter, number of adherent objects, and the average area of each adherent object indicating a more potent inhibition of adherence-induced platelet aggregation than clopidogrel. In conclusion, aspirin does not affect platelet adherence to collagen, whereas clopidogrel and ticagrelor inhibit to a similar extent dynamic platelet adhesion at 5 days post-treatment in ACS patients. However, ticagrelor exhibits a greater inhibitory effect on reducing adhesion-induced platelet aggregation.

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Pharmacodynamic properties of antiplatelet agents: current knowledge and future perspectives

Cited by 48 publications

References 129 publications

P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus

P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus

Microfludic platforms for the evaluation of anti-platelet agent efficacy under hyper-shear conditions associated with ventricular assist devices

Dynamic platelet adhesion in patients with an acute coronary syndrome: The effect of antiplatelet therapy

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