P2Y12 Receptor Antagonist Research Articles

2021 Asian Pacific Society of Cardiology Consensus Recommendations on the Use of P2Y12 Receptor Antagonists in the Asia-Pacific Region: Special Populations.

Advanced age, diabetes, and chronic kidney disease not only increase the risk for ischaemic events in chronic coronary syndromes (CCS) but also confer a high bleeding risk during antiplatelet therapy. These special populations may warrant modification of therapy, especially among Asians, who have displayed characteristics that are clinically distinct from Western patients. Previous guidance has been provided regarding the classification of high-risk CCS and the use of newer-generation P2Y12 inhibitors (i.e. ticagrelor and prasugrel) after acute coronary syndromes (ACS) in Asia. The authors summarise evidence on the use of these P2Y12 inhibitors during the transition from ACS to CCS and among special populations. Specifically, they present recommendations on the roles of standard dual antiplatelet therapy, shortened dual antiplatelet therapy and single antiplatelet therapy among patients with coronary artery disease, who are either transitioning from ACS to CCS; elderly; or with chronic kidney disease, diabetes, multivessel coronary artery disease and bleeding events during therapy.

A2A receptor agonists and P2Y12 receptor antagonists modulate expression of thrombospondin-1 (TSP-1) and its secretion from Human Microvascular Endothelial Cells (HMEC-1).

To address the problem of resistance to standard antiplatelet therapy in some patients, our team proposed a purinoceptor-dependent dual therapy. Its efficacy is also determined by the condition of the vascular endothelium which, by secreting numerous factors, is involved in hemostasis. Among them, thrombospondin-1 is important in the context of thrombotic events. Therefore we sought to determine if the novel dual purinoceptor-dependent concept is associated with TSP-1 changes in vascular endothelial cells. TSP-1 expression in human microvascular endothelial cells was determined at transcriptional and protein level. We performed real-time PCR, the Western blot analysis and ELISA test. We found that TSP-1 mRNA and protein expression levels significantly changed in response to P1R agonists treatment. Furthermore, we have observed that co-administration of selective A2AR agonists (UK-432,097 or MRE0094) with P2Y12R antagonists altered TSP-1 expression levels, and the direction of these changes was not synergistic. MRE0094 applied with ARC69931MX or R-138727 increased mRNA expression from 39 to 56 or 57%, respectively (*P<0.05 vs. MRE0094; ***P<0.001 vs. control). Also, in the case of the P2Y12R antagonists used together with UK-432,097, there was an increase from 53 to 71 and 70% (*P<0.05 vs. UK-432,097; ***P<0.001 vs. control). The observed trends in gene expression were reflected in the protein expression and the level of its secretion from HMEC-1. The article presents evidence which proves that the purinoceptor-dependent concept is associated with TSP-1 changes in endothelial cells (EC). Moreover, Human Microvascular Endothelial Cells treatment applied together with agonists (MRE0094 or UK-432,097) and P2Y12R antagonist did not result in any synergistic effect, implicating a possible crosstalk between G proteins in GPCRs dependent signaling. Therefore, we suggest that understanding of the specific mechanism underlying TSP-1 alterations in EC in the context of the dual purinoceptor-dependent approach is essential for antiplatelet therapies and should be the subject of future research.

Influence of GAS5/MicroRNA-223-3p/P2Y12 Axis on Clopidogrel Response in Coronary Artery Disease.

BackgroundDual antiplatelet therapy based on aspirin and P2Y12 receptor antagonists such as clopidogrel is currently the primary treatment for coronary artery disease (CAD). However, a percentage of patients exhibit clopidogrel resistance, in which genetic factors play vital roles. This study aimed to investigate the roles of GAS5 (growth arrest‐specific 5) and its rs55829688 polymorphism in clopidogrel response in patients with CAD.Methods and ResultsA total of 444 patients with CAD receiving dual antiplatelet therapy from 2017 to 2018 were enrolled to evaluate the effect of GAS5 single nucleotide polymorphism rs55829688 on platelet reactivity index. Platelets from 37 patients of these patients were purified with microbeads to detect GAS5 and microRNA‐223‐3p (miR‐223‐3p) expression. Platelet‐rich plasma was isolated from another 17 healthy volunteers and 46 newly diagnosed patients with CAD to detect GAS5 and miR‐223‐3p expression. A dual‐luciferase reporter assay was performed to explore the interaction between miR‐223‐3p and GAS5 or P2Y12 3′‐UTR in (human embryonic kidney 293 cell line that expresses a mutant version of the SV40 large T antigen) HEK 293T and (megakaryoblastic cell line derived in 1983 from the bone marrow of a chronic myeloid leukemia patient with megakaryoblastic crisis) MEG‐01 cells. Loss‐of‐function and gain‐of‐function experiments were performed to reveal the regulation of GAS5 toward P2Y12 via miR‐223‐3p in MEG‐01 cells. We observed that rs55829688 CC homozygotes showed significantly decreased platelet reactivity index than TT homozygotes in CYP2C19 poor metabolizers. Platelet GAS5 expression correlated positively with both platelet reactivity index and P2Y12 mRNA expressions, whereas platelet miR‐223‐3p expression negatively correlated with platelet reactivity index. Meanwhile, a negative correlation between GAS5 and miR‐223‐3p expressions was observed in platelets. MiR‐223‐3p mimic reduced while the miR‐223‐3p inhibitor increased the expression of GAS5 and P2Y12 in MEG‐01 cells. Knockdown of GAS5 by siRNA increased miR‐223‐3p expression and decreased P2Y12 expression, which could be reversed by the miR‐223‐3p inhibitor. Meanwhile, overexpression of GAS5 reduced miR‐223‐3p expression and increased P2Y12 expression, which could be reversed by miR‐223‐3p mimic.Conclusions GAS5 rs55829688 polymorphism might affect clopidogrel response in patients with CAD with the CYP2C19 poor metabolizer genotypes, and GAS5 regulates P2Y12 expression and clopidogrel response by acting as a competitive endogenous RNA for miR‐223‐3p.

“Tailored” antiplatelet bridging therapy with cangrelor: moving toward personalized medicine

In the setting of patients with indication to receive dual antiplatelet therapy undergoing surgery or invasive procedures, the risk of perioperative cardiac ischemic events, particularly stent thrombosis, is high, because surgery has a prothrombotic effect and antiplatelet therapy is withdrawn in order to avoid bleeding complications. Cangrelor, an intravenous P2Y12 receptor antagonist, has been tested in a randomized trial as a “bridge” to cardiac surgery from discontinuation of oral P2Y12 receptor antagonists. Thus, a consensus document extended its off-label use in this setting and before non-cardiac surgery. Currently, despite the implementation of a standardized bridging protocol with cangrelor, a residual risk of adverse outcome mainly due to bleeding events, still persist during the perioperative phase. Accordingly, a personalized management driven by platelet reactivity serial measurements and careful assessment of ischemic and bleeding risks has potential to optimize outcomes and costs as compared to a standardized bridging protocol, based on average pharmacodynamic data of oral P2Y12 inhibitors. While specific indications for bridging have been extensively addressed in the aforementioned consensus statement, the aim of the present document is the proposal of a “tailored” clinical decision-making algorithm inspired to the principle of personalized medicine dealing with complex clinical scenarios.

Previous psychiatric disorders and antipsychotic drugs in COVID-19 patients: early findings on possible worse outcome

Abstract Background There are a range of traditional risk factors for COVID-19, but it is not well established if there are also psychiatric related risk factors. These factors could increase angiotensin-converting enzyme 2 expression and potentiate COVID-19 cell entry. Purpose We aimed to assess if psychiatric disorders and antipsychotic treatments represent risk factors for COVID-19 worst outcomes. Methods We describe the demographics, symptoms, therapeutic management, and survival outcomes of COVID-19 in the population who were admitted in a single academic hospital in Northern Italy between March 1 and June 30, 2020. Patients were determined to have COVID-19 if they had a positive SARS-CoV-19 swab. We used logistic regression analyses to control for confounding by concomitant risk factors for COVID-19 and for therapeutic management of comorbidities including psychiatric disorders and antipsychotic related drugs. Results Among 609 patients, in-hospital death occurred in 120 (19.7%). A psychiatric disorder in the previous years was overrepresented (p&amp;lt;0.0001) in non-survivors (35.5%) in comparison with survivors (22.1%). Age and a history of hypertension were as well, established (p&amp;lt;0.005) risk factors for COVID-19 adverse outcomes: 80.6±11.4 vs 68±17.4 years and 70% vs 52% of people with hypertension in non-survivors vs survivors. Various pre-existing conditions were also associated (p&amp;lt;0.001) with increased risk of death, such as stroke or transient ischemic attacks, chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) (20% vs 8%, 35% vs 17%, and 24% vs 10%, respectively). We did not observe that prior use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers were more prevalent in non-survivors compared with survivors. On the opposite, prior use of aspirin, P2Y receptor antagonists, and antipsychotic drugs was more common (p&amp;lt;0.001) in non-survivors compared with their counterparts (36% vs 21%, 12% vs 5%, and 28% vs 10%, respectively). After multivariable adjustment, use of antipsychotic drugs was associated with higher risks of in-hospital death (OR: 2.27; 95% CI, 1.17–4.4). Other independent predictors of death were older age (OR: 2.8; 95% CI, 1.69–4.63), CKD (OR: 2.2; 95% CI, 1.21–4.03) and COPD (OR: 2.04; 95% CI, 1.22–3.42). Conclusions Antipsychotic drugs might be an independent risk factor for COVID-19 adverse outcomes. Although preliminary, our findings have implications for clinical services as they provide crucial information for understanding who is at greatest risk for COVID-19. Funding Acknowledgement Type of funding sources: None.

Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice

Inflammation may contribute to multiple brain pathologies. One cause of inflammation is lipopolysaccharide/endotoxin (LPS), the levels of which are elevated in blood and/or brain during bacterial infections, gut dysfunction and neurodegenerative diseases, such as Parkinson’s disease. How inflammation causes neuronal loss is unclear, but one potential mechanism is microglial phagocytosis of neurons, which is dependent on the microglial P2Y6 receptor. We investigated here whether the P2Y6 receptor was required for inflammatory neuronal loss. Intraperitoneal injection of LPS on 4 successive days resulted in specific loss of dopaminergic neurons (measured as cells staining with tyrosine hydroxylase or NeuN) in the substantia nigra of wild-type mice, but no neuronal loss in cortex or hippocampus. This supports the hypothesis that neuronal loss in Parkinson’s disease may be driven by peripheral LPS. By contrast, there was no LPS-induced neuronal loss in P2Y6 receptor knockout mice. In vitro, LPS-induced microglial phagocytosis of cells was prevented by inhibition of the P2Y6 receptor, and LPS-induced neuronal loss was reduced in mixed glial–neuronal cultures from P2Y6 receptor knockout mice. This supports the hypothesis that microglial phagocytosis contributes to inflammatory neuronal loss, and can be prevented by blocking the P2Y6 receptor, suggesting that P2Y6 receptor antagonists might be used to prevent inflammatory neuronal loss in Parkinson’s disease and other brain pathologies involving inflammatory neuronal loss.

Aspirin or Ticagrelor in Staphylococcus aureus Infective Endocarditis: Where Do We Stand?

Infective endocarditis is a challenging disease with a high mortality and morbidity rate. Antibiotic prophylaxis is currently recommended in high-risk infective endocarditis patients. However, the use of antibiotics faces the challenge of a low efficacy and contributes further to the emerging infection rate by antibiotic-resistant strains, emphasizing the need for new therapeutic strategies. Platelets are essential in the initial phase of infective endocarditis, acting as first-line immune responders. During the first phase of disease, bacteria can interact with platelets and counteract platelet antimicrobial activities. Mechanistic in vitro and animal studies on the effect of aspirin on bacteria-platelet interactions and the prevention of vegetation development showed promising results. However, data from clinical studies on the outcome of infective endocarditis patients who were receiving medically indicated aspirin therapy remain controversial. Therefore, the benefit of antiplatelet agents in infective endocarditis prevention has been questioned. Besides aspirin, it has been discovered that the platelet P2Y12 receptor antagonist ticagrelor has antibacterial properties in addition to its potent antiplatelet activity. Furthermore, a recent study in mice and a case report remarkably indicated the ability of this drug to eradicate Staphylococcus aureus bacteremia. This review will focus on current knowledge on antibacterial activity of ticagrelor, compared to aspirin, pointing out main unanswered questions. The goal is to provide food for thought as to whether a prior ticagrelor therapy might be beneficial for the prevention of infective endocarditis.

Bleeding risk with concomitant use of tirofiban and third-generation P2Y12 receptor antagonists in patients with acute myocardial infarction: A real-life data.

Combination of dual antiplatelet therapy (DAPT) with glycoprotein (GP) IIb/IIIa inhibitors can increase bleeding risk. In this study, we aimed to investigate bleeding complications of different DAPTs with concomitant tirofiban use in patients with acute coronary syndrome (ACS). This retrospective study included 224 consecutive ACS patients (mean age 56.6±11.1 years, 193 men) who were given conventional dose of tirofiban (25 µg/kg per 3 minutes followed by an infusion of 0.15 µg/kg/min for 24 hours) in addition to DAPT (300 mg aspirin followed by 100 mg/day + 600 mg clopidogrel followed by 75 mg/day or 180 mg ticagrelor followed by 90 mg twice daily or 60 mg prasugrel followed by 10 mg/day). Any intra-hospital bleeding complications were noted. Of the 224 patients, 115 were given ticagrelor and 32 were given prasugrel. Mean hemoglobin fall was similar between the patients taking ticagrelor/prasugrel and those taking clopidogrel. Ten patients taking ticagrelor and one patient taking prasugrel had hemoglobin fall ≥3 g/dL versus two patients in clopidogrel group (p=0.228). Gastrointestinal bleeding (two patients taking ticagrelor), hematoma at access site (three patients taking ticagrelor), and cardiac tamponade (two patients taking ticagrelor) rates were also similar. Creatinine levels were associated with hemoglobin fall ≥3 g/dL (p=0.032, Odds ratio 2.189, 95% confidence interval 1.070-4.479). There was no relation between hemoglobin fall ≥3 g/dL and antiplatelet agent, age, sex, hypertension, or diabetes. Tirofiban may be given to patients receiving ticagrelor or prasugrel with a bleeding rate similar to clopidogrel. Close monitoring for bleeding risk is recommended, especially in patients with higher creatinine levels.

Platelet inhibition by P2Y12 antagonists is potentiated by adenosine signalling activators.

P2Y12 receptor antagonists reduce platelet aggregation and the incidence of arterial thrombosis. Adenosine signalling in platelets directly affects cyclic nucleotide tone, which we have shown to have a synergistic relationship with P2Y12 inhibition. Several studies suggest that ticagrelor inhibits erythrocyte uptake of adenosine and that this could also contribute to its antiplatelet effects. We therefore examined the effects on platelet activation of adenosine signalling activators in combination with the P2Y12 receptor antagonists ticagrelor and prasugrel. Human washed platelets, platelet-rich plasma and whole blood were used to test the interactions between ticagrelor or prasugrel and adenosine or 5'-N-ethylcarboxamidoadenosine (NECA). Platelet reactivity to thrombin, protease-activated receptor 1 (PAR-1) activation or collagen was assessed by a combination of 96-well plate aggregometry, light transmission aggregometry, whole blood aggregometry, ATP release assay and levels of cAMP. The inhibitory effects of ticagrelor and prasugrel on platelet aggregation and ATP release were enhanced in the presence of adenosine or NECA. Isobolographic analysis indicated a powerful synergy between P2Y12 receptor inhibition and adenosine signalling activators. Increased levels of cAMP in platelets were also observed. In all cases, ticagrelor showed similar synergistic effects on platelet inhibition as prasugrel in the presence of adenosine or NECA. These results indicate that P2Y12 antagonists have a synergistic relationship with adenosine signalling and that their efficacy may depend partly upon the presence of endogenous adenosine. This effect was common for prasugrel and ticagrelor despite reports of differences in their effects upon adenosine reuptake.

Synthesis, characterization and biological evaluation of indomethacin derived thioureas as purinergic (P2Y1, P2Y2, P2Y4, and P2Y6) receptor antagonists

G-protein-coupled receptors for extracellular nucleotides are known as P2Y receptors and are made up of eight members that are encoded by distinct genes and can be classified into two classes based on their affinity for specific G-proteins. P2Y receptor modulators have been studied extensively, but only a few small-molecule P2Y receptor antagonists have been discovered so far and approved by drug agencies. Derivatives of indole carboxamide have been identified as P2Y12 and P2X7 antagonist, as a result, we developed and tested a series of indole derivatives4a-lhaving thiourea moiety as P2Y receptor antagonist by using a fluorescence-based assay to measure the inhibition of intracellular calcium release in 1321N1 astrocytoma cells that had been stably transfected with the P2Y1, P2Y2, P2Y4 and P2Y6 receptors. Most of the compounds exhibited moderate to excellent inhibition activity against P2Y1 receptor subtype. The series most potent compound, 4h exhibited an IC50 value of 0.36 ± 0.01 µM selectivity against other subtypes of P2Y receptor. To investigate the ligand-receptor interactions, the molecular docking studies were carried out. Compound 4h is the most potent P2Y1 receptor antagonist due to interaction with an important amino acid residue Pro105, in addition to Ile108, Phe119, and Leu102.

Therapeutic Effects of Berberine Hydrochloride on Stress-Induced Diarrhea-Predominant Irritable Bowel Syndrome Rats by Inhibiting Neurotransmission in Colonic Smooth Muscle.

The etiology of diarrhea-predominant irritable bowel syndrome (IBS-D) is complicated and closely related to neurotransmission in the gastrointestinal (GI) tract. Developing new strategies for treating this disease is a major challenge for IBS-D research. Berberine hydrochloride (BBH), the derivative of berberine, is a herbal constituent used to treat IBS. Previous studies have shown that BBH has potential anti-inflammatory, antibacterial, analgesic, and antidiarrheal effects and a wide range of biological activities, especially in regulating the release of some neurotransmitters. A modified IBS-D rat model induced by chronic restraint stress was used in all experiments to study the effects of BBH on the GI tract. This study measured the abdominal withdrawal reflex (AWR) response to graded colorectal distention (CRD; 20, 40, 60, and 80 mmHg) and observed the fecal areas of stress-induced IBS-D model. Experiments were conducted using organ bath techniques, which were performed in vitro using strips of colonic longitudinal smooth muscle. Inhibitory and excitatory neurotransmitter agents were added to each organ bath to observe contractile responses on the strips and the treatment effect exerted by BBH. The IBS-D rat model was successfully induced by chronic restraint stress, which resulted in an increased defecation frequency and visceral hypersensitivity similar to that of humans. BBH could reduce 4-h fecal areas and AWR response to CRD in IBS-D. The stress-induced IBS-D model showed upregulated colonic mRNA expression levels of 5-hydroxytryptamine-3A receptor and downregulated expression levels of neuronal nitric oxide synthase. Meanwhile, BBH could reverse this outcome. The responses of substances that regulate the contraction induced by related neurotransmission in the longitudinal smooth muscle of IBS-D colon (including the agonist of acetylcholine, carbachol; NOS inhibitor, L-NAME; and P2Y1 receptor antagonist, MRS2500) can be inhibited by BBH. In summary, BBH promotes defecation frequency and visceral hypersensitivity in IBS-D and exerts inhibitory effects on contractile responses in colonic longitudinal smooth muscle. Thus, BBH may represent a new therapeutic approach for treating IBS-D.

P2Y receptors in GtoPdb v.2021.3

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 192]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [47, 110, 190, 383, 396]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype, approved in Japan for the management of dry eye disease [241], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [53, 323].

Optimal Antiplatelet Therapy After PCI in High-Bleeding-Risk Patients

Several recent randomized trials suggest that abbreviated dual antiplatelet therapy (DAPT; aspirin plus a platelet P2Y12 receptor antagonist) can

Multi-institutional Patterns of Clopidogrel Response Among Patients Undergoing Transcarotid Artery Revascularization

Current guidelines recommend dual antiplatelet therapy (DAPT) in patients undergoing carotid artery stenting. The most common DAPT regimen is aspirin and clopidogrel, a P2Y12 receptor antagonist; however, there is evidence that the prevalence of clopidogrel resistance (CR) in patients undergoing percutaneous coronary interventions may exceed 40%. Few studies have investigated the prevalence and impact of CR in patients undergoing extracranial carotid artery stenting, particularly transcarotid artery revascularization (TCAR).

Efficacy and Safety of Aspirin Combined with Low-Dose P2Y12 Receptor Antagonists in East Asian Patients Undergoing PCI.

Previous studies have indicated that low-dose new generation of P2Y12 receptor antagonists may be more suitable compared with clopidogrel at a standard dose for the dual antiplatelet therapy (DAPT) for East Asian patients receiving percutaneous coronary intervention (PCI). However, there remains no consensus in clinical practice. Thus, in this study, we aimed to determine the efficacy and safety of low-dose P2Y12 receptor antagonists, compared to clopidogrel at a standard dose, in DAPT in East Asian patients after PCI. We systematically searched literatures for randomized controlled trials (RCT) comparing low-dose P2Y12 receptor antagonists with standard-dose clopidogrel for the treatment of East Asian patients undergoing PCI. The endpoints of efficacy include major adverse cardiac events (MACEs), all-cause mortality, and the number of target vessel revascularization. The indicators of safety include major and minor bleeding events. Heterogeneity was evaluated by I2 statistic test. Begg's and Egger's tests were used to evaluate publication bias. In total, 2,747 subjects from 8 RCT studies were included. Low-dose new P2Y12 receptor antagonists, that is, ticagrelor or prasugrel, showed significantly lower incidence of MACEs, as compared with standard-dose clopidogrel, in the East Asian patients who are in DAPT after undergoing PCI. Further, no difference was noted for the risk of major and minor bleeding events. In East Asian patients undergoing PCI and receiving DAPT, the use of low-dose P2Y12 receptor antagonists, ticagrelor or prasugrel, has been determined to be superior than clopidogrel at standard dose; this has been evidenced by a lower incidence of MACEs without increasing the risk of bleeding.

Autocrine regulation of wound healing by ATP release and P2Y2 receptor activation

AimsApplication of exogenous nucleotides can modulate wound healing via the activation of purinergic receptors. However, evidence for the release of endogenous nucleotides and the subsequent activation of purinergic receptors in this process has not been well defined. Therefore, the current study aimed to investigate wound-mediated nucleotide release and autocrine purinergic signalling during HaCaT keratinocyte wound closure following scratch injury. Main methodsAn in vitro scratch wound apparatus was employed to study wound healing over 24-h in the presence of modulators of ATP release, P2 receptors and pathways downstream of P2 receptor activation. Key findingsAdenosine 5′-triphosphate (ATP) was released from scratched cells. The ectonucleotidase apyrase and pharmacological inhibition of the nucleotide release hemichannel, pannexin-1, decreased wound closure over time. The non-selective P2Y receptor antagonist suramin and the selective P2Y2 receptor antagonist AR-C118925XX, but not other P2 antagonists, decreased wound closure. AR-C118925XX decreased wound closure in a concentration-dependent fashion. However, exogenous P2Y2 receptor agonists, ATP or uridine 5′-triphosphate, did not enhance wound closure. PCR and immunoblotting confirmed P2Y2 receptor expression in HaCaT cells. U73122, a phospholipase C antagonist, and 2-aminoethoxydiphenylborate, an inositol 1,4,5-trisphosphate receptor-sensitive Ca2+-release channel antagonist, decreased wound closure consistent with P2Y2 receptor activation. Absence of extracellular or intracellular Ca2+ or inhibition of intracellular Ca2+-release also impaired wound closure. SignificanceThese data describe a novel autocrine signalling mechanism in which wound-mediated release of endogenous ATP in response to mechanical scratching of HaCaT cells activates P2Y2 receptors to facilitate wound closure.

A review of the effects of ticagrelor on adenosine concentration and its clinical significance.

Ticagrelor is an oral antiplatelet drug that can reversibly bind to the platelet P2Y12 receptor. Ticagrelor is metabolized mainly by CYP3A4 and produces a rapid blood concentration-dependent platelet inhibitory effect. Unlike other P2Y12 receptor antagonists, many clinical features of ticagrelor are not related to P2Y12 receptor antagonism. This review aims to gather existing literature on the clinical effects of ticagrelor after inhibiting adenosine uptake. The current study reviewed literature related to the effects of ticagrelor on adenosine metabolism. The review also examined the drug's biological effects and clinical characteristics to see how it could be used in a clinical setting. Many studies have shown that ticagrelor can inhibit equilibrative nucleoside transporter 1 (ENT1). This inhibition leads to intracellular adenosine uptake, increased adenosine half-life and plasma concentration levels and an enhanced adenosine-mediated biological effect. Based on the studies reviewed, it wasfound that ticagrelor essentially inhibits adenosine absorption of adenosine into cells through ENT1, which increases the concentration in the blood and subsequently increases the protection of the heart muscle by adenosine. It also prevents platelet aggregation, and extends the biological effects of coronary arteries. Moreover, it leads to a lower mortality rate in acute coronary syndrome (ACS) patients.

Platelet P2Y12 Receptor Deletion or Pharmacological Inhibition does not Protect Mice from Sepsis or Septic Shock

Introduction Platelets are increasingly appreciated as key effectors during sepsis, raising the question of the usefulness of antiplatelet drugs to treat patients with sepsis. Objective Evaluate the potential contribution of the platelet P2Y 12 receptor in the pathogenesis of polymicrobial-induced sepsis and septic shock in mice. Methods The effects of P2Y 12 inhibition using clopidogrel treatment and of platelet-specific deletion of the P2Y 12 receptor in mice were examined in two severity grades of cecal ligation and puncture (CLP) leading to mild sepsis or septic shock. Results Twenty hours after induction of the high grade CLP, clopidogrel- and vehicle-treated mice displayed a similar 30% decrease in mean arterial blood pressure (MAP) characteristic of shock. Septic shock-induced thrombocytopenia was not modified by clopidogrel treatment. Plasma concentrations of inflammatory cytokines and myeloperoxidase (MPO) were similarly increased in clopidogrel- and vehicle-treated mice, indicating comparable increase in systemic inflammation. Thrombin-antithrombin (TAT) complexes and the extent of organ damage were also similar. In mild-grade CLP, clopidogrel- and vehicle-treated mice did not display a significant decrease in MAP, while thrombocytopenia and plasma concentrations of TNFα, IL6, IL10, MPO, TAT and organ damage reached similar levels in both groups, although lower than those reached in the high grade CLP. Similarly, mice with platelet-specific deletion of the P2Y 12 receptor were not protected from CLP-induced sepsis or septic shock. Conclusion The platelet P2Y 12 receptor does not contribute to the pathogenesis of sepsis or septic shock in mice, suggesting that P2Y 12 receptor antagonists may not be beneficial in patients with sepsis or septic shock.

Use of Thromboelastography Platelet Mapping for Assessment of Individual Platelet Response Secondary to Oral Antiplatelet Therapy after Percutaneous Coronary Intervention: An Attempt to Start Personalized Antiplatelet Therapy in India

AbstractHigh on-treatment platelet reactivity (HPR) with P2Y12 receptor antagonists in patients treated with dual antiplatelet therapy (DAPT) is strongly associated with adverse ischemic events after percutaneous coronary intervention (PCI). This prospective study was conducted to assess individual platelet response and HPR to antiplatelet medications in post-PCI cases by thromboelastography platelet mapping (TEG-PM). Total 82 patients who were on aspirin and on either clopidogrel, prasugrel, or ticagrelor were evaluated. The percentage of platelet inhibition to arachidonic acid (AA) and adenosine diphosphate (ADP) was calculated by [100-{(MA ADP/AA–MA Fibrin) / (MA Thrombin–MA Fibrin) × 100}], taking 50% response as cut-off for HPR. HPR to clopidogrel and prasugrel was 14.29 and 12.5%, respectively. No HPR was detected to aspirin and ticagrelor. The mean percentage of platelet inhibition was significantly higher in patients with ticagrelor 82.99, 95% confidence interval (CI) of [77.3, 88.7] as compared with clopidogrel 72.21, 95% CI of [65.3, 79.1] and prasugrel 64.2, 95% CI of [52.5, 75.9] (p-value of 0.041 and 0.003, respectively). Aspirin along with ticagrelor is associated with a higher mean percentage of platelet inhibition, and lower HPR as compared with the usage of aspirin combined with clopidogrel or prasugrel. Additionally, it might also be concluded that TEG-PM could be used effectively to measure the individual platelet functions which would make oral antiplatelet therapy more personalized for cardiac patients.

Pharmacokinetics, Pharmacodynamics and Safety of Ticagrelor in Children with Sickle Cell Disease: Results of a Two-Part Phase 2 Study

▪ INTRODUCTIONActivated platelets promote the adhesion of sickle cells to endothelial cells and the formation of platelet-leukocyte aggregates, contributing to vaso-occlusion (VOC). It has been suggested that inhibition of platelet reactivity may reduce the rate of VOCs in sickle cell disease (SCD). A study with ticlopidine reported a reduced rate of VOCs versus placebo. A recent, placebo-controlled, pediatric study with prasugrel showed a non-significant reduction in VOCs events, which was likely due to the low level of platelet inhibition. Ticagrelor is a reversible P2Y12 receptor antagonist shown to inhibit ADP-induced platelet aggregation and is approved for use in adults with coronary artery disease (CAD). A phase 2 study was conducted to characterize the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of ticagrelor in children aged 2-17 years with SCD (HbSS or HbS/β0; NCT02214121). METHODSThis study was conducted in 2 parts: Part A was an open-label, randomized, dose-ranging study in which patients received two single doses of ticagrelor 1 week apart, followed by twice daily (bid) ticagrelor for 1 week. Initially, single doses of 0.125-0.563 mg/kg were given, followed by repeated dosing with 0.125 mg/kg bid. Individual platelet response was used to inform further dosing. After an interim analysis including the first 14 patients in Part A, single doses were increased to a maximum of 2.25 mg/kg and repeated dosing up to 0.75 mg/kg bid. Part B (optional) immediately followed the repeated dosing in Part A: patients were randomized 2:1 to continue ticagrelor with the same dose used during Part A or matching placebo as a double-blind treatment for 4 weeks. Safety was assessed during both parts, pain and analgesic use were recorded daily in an eDiary, and painful crises were reported at each visit. Exposure to ticagrelor and the active metabolite (AR-C124910XX), as well as the subsequent platelet inhibition, were determined after single and repeated doses in Parts A and B. RESULTSA total of 45 children with SCD, mean age 11.2 years (range: 3-17) received study drug in Part A and 23 (15 ticagrelor, 8 placebo) children, mean age 10.0 years (range: 3-17) in Part B. Most patients were of African descent (35/45 in Part A and 22/23 in Part B). Ticagrelor exposure increased approximately dose-linearly, with maximum plasma concentration values ranging from 15.2 to 566.6 ng/mL (with 0.125 mg/kg to 2.25 mg/kg) for ticagrelor and 3.1-156.0 ng/mL for AR-C124910XX. The parent:metabolite ratio in children with SCD was similar to that previously observed in adults. Mean P2Y12 reaction units (PRU) after single doses of ticagrelor decreased from pre-dose to 2 hours post-dose (change from baseline: -23.4 to -207.8 PRU for 0.125 mg/kg to 2.25 mg/kg), and returned towards baseline up to the last timepoint (6 or 8 hours' post-dose). In Part B, no difference was seen between the placebo and ticagrelor groups in pain ratings and analgesic use, although the study was not statistically powered to detect differences in these outcomes. Ticagrelor was well tolerated, with no bleeding during treatment and no patient discontinued treatment due to an adverse event. CONCLUSIONSThe PK/PD profile of ticagrelor in children with SCD was suitably characterized and the exposure-response relationship appeared similar to that previously observed in adults with CAD. Ticagrelor was well tolerated and no safety concerns were raised. The potential to impact SCD-related pain crises needs further evaluation, as the number of patients, low doses for some patients and short study duration limit the efficacy conclusions from this study. DisclosuresHsu:AstraZeneca: Other: steering committee for HESTIA trial; Emmi: Other: consultant for Emmi. Sarnaik:AstraZeneca: Other: Advisory Board. Amilon:AstraZeneca: Employment. Rensfeldt:AstraZeneca: Employment. Berggren:AstraZeneca: Employment.