ticagrelor and Inflammation

The effect and clinical benefit of P2Y12 receptor antagonists may not be limited to platelet inhibition and the prevention of arterial thrombus formation. Potential additional effects include reduction of the pro-inflammatory role of activated platelets and effects related to P2Y12 receptor inhibition on other cells apart from platelets. P2Y12 receptor antagonists, thienopyridines and ticagrelor, differ in their mode of action being prodrugs instead of direct acting and irreversibly instead of reversibly binding to P2Y12 . These key differences may provide different potential when it comes to additional effects. In addition to P2Y12 receptor blockade, ticagrelor is unique in having the only well-documented additional target of inhibition, the equilibrative nucleoside transporter 1. The current review will address the effects of P2Y12 receptor antagonists beyond platelets and the protection against arterial thrombosis. The discussion will include the potential for thienopyridines and ticagrelor to mediate anti-inflammatory effects, to conserve vascular function, to affect atherosclerosis, to provide cardioprotection and to induce dyspnea.

Topics: Adenosine; Animals; Atherosclerosis; Blood Platelets; Cardiotonic Agents; Cardiovascular Physiological Phenomena; Equilibrative Nucleoside Transporter 1; Humans; Inflammation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thienopyridines; Ticagrelor

Acute myocardial ischaemia triggers a non-specific inflammatory response of remote myocardium through the increase of plasma concentrations of acute-phase proteins, which causes myocardial oedema. As ticagrelor has been shown to significantly decrease circulating levels of several pro-inflammatory cytokines in patients after acute myocardial infarction with ST-elevation (STEMI), we sought to investigate a potential suppressive effect of ticagrelor over prasugrel on cardiac magnetic resonance (CMR) T1 and T2 values in remote myocardium.. Ninety STEMI patients were prospectively included and randomised to receive either ticagrelor or prasugrel maintenance treatment after successful primary percutaneous coronary intervention. Patients underwent CMR after 2-7 days. The protocol included long and short axis cine imaging, T1 mapping, T2 mapping and late gadolinium enhancement imaging.. After excluding 30 patients due to either missing images or insufficient quality of the T1 or T2 maps, 60 patients were included in our analysis. Of those, 29 patients were randomised to the ticagrelor group and 31 patients to the prasugrel group. In the remote myocardium, T1 values did not differ between groups (931.3 [919.4-950.4] ms for ticagrelor vs. 932.6 [915.5-949.2] ms for prasugrel (p = 0.94)), nor did the T2 values (53.8 ± 4.6 ms for ticagrelor vs. 53.7 ± 4.7 ms for prasugrel (p = 0.86)). Also, in the infarcted myocardium, T1 and T2 values did not differ between groups.. In revascularised STEMI patients, ticagrelor maintenance therapy did not show superiority over prasugrel in preventing early remote myocardial inflammation as assessed by CMR T1 and T2 mapping.

Topics: Arrhythmias, Cardiac; Contrast Media; Gadolinium; Humans; Inflammation; Magnetic Resonance Spectroscopy; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Predictive Value of Tests; ST Elevation Myocardial Infarction; Ticagrelor; Treatment Outcome

No study has compared pharmacologic properties of ticagrelor and clopidogrel in non-dialysis patients with stage 4-5 chronic kidney disease (CKD).. We conducted a double-blind RCT to compare effects of ticagrelor and clopidogrel in 48 CKD, with the primary outcome of ADP-induced platelet aggregation (WBPA) after 2 weeks of DAPT. In a parallel arm, we compared effects of 2 weeks of ticagrelor plus aspirin on mean changes in WBPA and markers of thromboinflammation among non-CKD controls (n = 26) with that of CKD in the ticagrelor-arm.. Average age of CKD was 53.7 years, with 62% women, 54% African American, and 42% with stage 5 CKD. Ticagrelor generated statistically lower WBPA values post treatment [median 0 Ω (IQR 0, 2)] vs. clopidogrel [median 0 Ω (IQR 0, 5)] (P = 0.002); percent inhibition of WBPA was greater (87 ± 22% vs. 63 ± 50%; P = 0.04; and plasma IL-6 levels were much lower (8.42 ± 1.73 pg/ml vs. 18.48 ± 26.56 pg/ml; P = 0.04). No differences in mean changes in WBPA between CKD-ticagrelor and control groups were observed. Ticagrelor- DAPT reduced levels of IL-1α and IL-1β in CKD-ticagrelor and control groups, attenuated lowering of TNFα and TRAIL levels in CKD-ticagrelor (vs controls), and had global changes in correlation between various cytokines in a subgroup of CKD-ticagrelor subjects not on statins (n = 10). Peak/trough levels of ticagrelor/metabolite were not different between CKD-ticagrelor and control groups.. We report significant differences in platelet aggregation and anti-inflammatory properties between ticagrelor- and clopidogrel-based DAPT in non-dialysis people with stage 4-5 CKD. These notable inflammatory responses suggest ticagrelor-based DAPT might lower inflammatory burden of asymptomatic patients with stage 4 or 5 CKD. (clinicaltrials.gov # NCT03649711).

Topics: Adenosine; Clopidogrel; Female; Humans; Inflammation; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Renal Insufficiency, Chronic; Thrombosis; Ticagrelor; Ticlopidine; Treatment Outcome

The use of acetylsalicylic acid (ASA) is associated with improved outcome in patients with sepsis, and P2Y

Topics: Adenosine; Administration, Intravenous; Adolescent; Adult; Aspirin; Cells, Cultured; Clopidogrel; Cytokines; Drug Therapy, Combination; Endotoxemia; Endotoxins; Healthy Volunteers; Humans; Inflammation; Inflammation Mediators; Male; Netherlands; Platelet Activation; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Ticagrelor; Ticlopidine; Time Factors; Treatment Outcome; Young Adult

Platelets play an important role in inflammation. Inhibitors of the P2Y. We compared the effects of clopidogrel and ticagrelor therapy for carotid atherosclerotic plaque inflammation using. Fifty patients with acute coronary syndrome and ≥1. Baseline characteristics were similar between the 2 groups. At 6-month follow-up, low-density lipoprotein cholesterol and C-reactive protein significantly decreased in both groups (P < 0.001). The TBR of the index vessel and aorta significantly decreased in both groups (P < 0.01). The percent change in the MDS TBR of the index vessel was numerically but not significantly lower in the clopidogrel group than in the ticagrelor group (-9.5 ± 14.6% vs -13.5 ± 19.3%; P = 0.427). Likewise, the percent change in the whole-vessel TBR of the index vessel was not different between the 2 groups (P = 0.166). Similar findings were observed for changes in the MDS TBR (P = 0.412) or whole-vessel TBR of the aorta (P = 0.363).. Carotid atherosclerotic plaque inflammation significantly decreases to a similar degree following 6 months of either clopidogrel or ticagrelor treatment.

Topics: Adenosine; Aged; Anti-Inflammatory Agents; Carotid Arteries; Carotid Stenosis; Clopidogrel; Female; Fluorodeoxyglucose F18; Humans; Inflammation; Male; Middle Aged; Plaque, Atherosclerotic; Positron Emission Tomography Computed Tomography; Predictive Value of Tests; Prospective Studies; Purinergic P2Y Receptor Antagonists; Radiopharmaceuticals; Republic of Korea; Severity of Illness Index; Ticagrelor; Ticlopidine; Time Factors; Treatment Outcome

Platelets and platelet-monocyte interaction play an important role in inflammation. Both pro- and anti-inflammatory effects of platelet inhibition have been reported in animal models. This study aimed to investigate the effect of platelets and platelet inhibition by the new P2Y12 receptor antagonist ticagrelor on monocyte function, as assessed by cytokine responses to Toll-like Receptor (TLR) ligands. In a set of in vitro experiments, peripheral blood mononuclear cells (PBMC) incubated with the TLR2 ligand Pam3CSK4 produced less cytokines in the presence of platelets, whereas platelets increased the production of cytokines when PBMC were exposed to TLR4 ligand lipopolysaccharide (LPS). These effects of platelets were dependent on direct platelet-leukocyte aggregation and for the Pam3CSK4-induced response, on phagocytosis of platelets by monocytes. In a double blind, placebo-controlled crossover trial in healthy volunteers, a single oral dosage of 180 mg ticagrelor reduced platelet-monocyte complex (PMC) formation. This was associated with an increase in pro-inflammatory cytokines in blood exposed to Pam3CSK4, but a decrease in these cytokines in blood exposed to LPS. These findings show that platelets differentially modulate TLR2- and TLR4-mediated cytokine responses of PBMC. Through inhibition of platelet-leukocyte interaction, P2Y12 receptor antagonists may either exert a pro- or anti-inflammatory effect during infections depending on the TLR primarily involved.

Topics: Adenosine; Adenosine Diphosphate; Adult; Blood Platelets; Cross-Over Studies; Cytokines; Double-Blind Method; Humans; Inflammation; Leukocytes, Mononuclear; Ligands; Lipopolysaccharides; Male; Monocytes; Phagocytosis; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; RNA, Messenger; Ticagrelor; Toll-Like Receptor 2; Toll-Like Receptor 4; Young Adult

Clinical studies suggest that platelet P2Y12 inhibitors reduce mortality from sepsis, although the underlying mechanisms have not been clearly defined in vivo. We hypothesized that P2Y12 inhibitors may improve survival from sepsis by suppressing systemic inflammation and its prothrombotic effects. We therefore determined whether clopidogrel and the novel, more potent P2Y12 inhibitor, ticagrelor, modify these responses in an experimental human model.. We randomized 30 healthy volunteers to ticagrelor (n=10), clopidogrel (n=10), or no antiplatelet medication (controls; n=10). We examined the effect of P2Y12 inhibition on systemic inflammation, which was induced by intravenous injection of Escherichia coli endotoxin. Both P2Y12 inhibitors significantly reduced platelet-monocyte aggregate formation and peak levels of major proinflammatory cytokines, including tumor necrosis factor α, interleukin-6, and chemokine (C-C motif) ligand 2. In contrast to clopidogrel, ticagrelor also significantly reduced peak levels of IL-8 and growth colony-stimulating factor and increased peak levels of the anti-inflammatory cytokine IL-10. In addition, ticagrelor altered leukocyte trafficking. Both P2Y12 inhibitors suppressed D-dimer generation and scanning electron microscopy revealed that ticagrelor also suppressed prothrombotic changes in fibrin clot ultrastructure.. Potent inhibition of multiple inflammatory and prothrombotic mechanisms by P2Y12 inhibitors demonstrates critical importance of platelets as central orchestrators of systemic inflammation induced by bacterial endotoxin. This provides novel mechanistic insight into the lower mortality associated with P2Y12 inhibitors in patients with sepsis in clinical studies.

Topics: Adenosine; Anti-Inflammatory Agents; Biomarkers; Blood Platelets; Chemotaxis, Leukocyte; Clopidogrel; Cytokines; Endotoxins; England; Female; Fibrin Fibrinogen Degradation Products; Humans; Inflammation; Inflammation Mediators; Male; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Ticlopidine; Time Factors; Treatment Outcome; Young Adult

Inflammation plays a critical role in atherosclerosis. This study examines the effects of ticagrelor and clopidogrel on inflammatory parameters, obtained from complete blood count (CBC) and biochemical measurements, in patients with acute coronary syndrome.. One hundred acute coronary syndrome (ACS) patients were included in the study and grouped according to clopidogrel (. NLR, MHR, PLR, and SII levels were lower in ACS patients treating with ticagrelor. Ticagrelor may improve these inflammatory parameters in percutaneous coronary intervention (PCI)-treated ACS patients compared to clopidogrel.

Topics: Acute Coronary Syndrome; Clopidogrel; Humans; Inflammation; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Ticagrelor

Aside from being an antiplatelet, ample studies revealed the anti-ischemic cardioprotective effect of Ticagrelor (Tica) mediated via different mechanisms; however, its protective potential against renal ischemia reperfusion (I/R) has been rarely investigated, which is the aim of the current study. Animals were divided into sham, I/R (45 min/24 h) and I/R pretreated with Tica (30 mg/kg) for one week, after a pilot study using 30 and 150 mg/kg of Tica. The pre-administration of Tica (30 mg/kg) guarded against the harmful impact of I/R insult and improved renal histological structure and function validated by reducing cystatin-C, neutrophil gelatinase-associated lipocalin, interleukin-18 and the classical markers, blood urea nitrogen and creatinine. On the molecular level, Tica signified its anti-inflammatory capacity by inhibiting nuclear factor κB and tumor necrosis factor-α, while it enhanced the autophagy process evidenced by increasing the protein expression of Beclin-1 and microtubule-associated protein light chain 3 II and abating the lysosomal marker cathepsin-D. Besides, Tica augmented cell survival by inhibiting galectin-3 and caspase-3 activity. Additionally, Tica modulated the renin-angiotensin system (RAS), where it decreased angiotensin II and downregulated the gene expression of prorenin and endothelin-1

Topics: Acute Kidney Injury; Animals; Autophagy; Dose-Response Relationship, Drug; Drug Repositioning; Galectin 3; Inflammation; Kidney; Platelet Aggregation Inhibitors; Protective Agents; Rats; Receptor, Endothelin A; Renin; Renin-Angiotensin System; Reperfusion Injury; Ticagrelor

Acute lung injury (ALI) is characterized by abnormal inflammatory response without effective therapies. P2Y12 receptor (P2Y12R) plays a vital role in inflammatory response. This study intends to explore whether P2Y12R antagonists can inhibit LPS-induced inflammatory injury of human pulmonary microvascular endothelial cells (HPMVECs) and endothelial cell dysfunction.. Using a cell model of ALI, the role of P2Y12R was investigated in LPS-induced HPMVECs. The expression of P2Y12R was detected by RT-qPCR and Western blot analysis assay and TNF-α, IL-1β, and IL-6 levels were analyzed by RT-qPCR. NO levels were also analyzed through NO kit. The levels of NF-κB p65, P-IκB-α, and IκB-α, as well as p-AKT and eNOS levels were detected by Western blot analysis assay. Wound healing assay was performed to evaluate HPMVECs migration. FITC-dextran was used to evaluate endothelial cell permeability, and the analysis of adherens junction protein VE-cadherin and endothelial cell tight junction proteins ZO-1, Claudin 5 and Occludin expression was performed by RT-qPCR and Western blot analysis assay.. In vitro, LPS increased the expression levels of P2Y12R and pro-inflammatory mediators (TNF-α, IL-1β, and IL-6), followed by a decrease in HPMVECs migration. In addition, LPS led to an increase in endothelial cell permeability. P2Y12R antagonists Ticagrelor or clopidogrel treatment significantly reversed these effects of LPS.. The inhibitor of P2Y12R was able to decrease inflammatory response, promote migration and improve endothelial cell function and permeability, suggesting a key role of P2Y12R in ALI.

Topics: Acute Lung Injury; Claudin-5; Clopidogrel; Endothelial Cells; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Lipopolysaccharides; NF-kappa B; NF-KappaB Inhibitor alpha; Occludin; Proto-Oncogene Proteins c-akt; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Ticagrelor; Tumor Necrosis Factor-alpha

Ticagrelor is the first reversibly binding oral P2Y

Topics: Acute Coronary Syndrome; Animals; CARD Signaling Adaptor Proteins; Chlorides; Disease Models, Animal; Humans; Inflammasomes; Inflammation; Macrophages; Mice, Inbred C57BL; Models, Biological; NLR Family, Pyrin Domain-Containing 3 Protein; Protein Multimerization; Receptors, Purinergic P2Y12; Signal Transduction; Ticagrelor

To investigate the effect of ticagrelor combined with tirofiban versus clopidogrel combined with tirofiban on inflammation response and prognosis of patients with unstable angina pectoris (UA). The present prospective study included a total of 291 patients who were diagnosed as unstable UA from January 2018 to December 2019. All UA patients were divided into two groups: ticagrelor combined with tirofiban group (n = 159) and clopidogrel combined with tirofiban group (n = 132). Serum levels of C-reactive protein (CRP), interleukin-1β, interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-9 were measured using commercially available enzyme-linked immunosorbent assay kits. Kaplan-Meier (K-M) curve was performed for analysis of cumulative incidences of major adverse cardiovascular events (MACEs). Both ticagrelor combined with tirofiban and clopidogrel combined with tirofiban significantly decreased the serum levels of inflammatory factors in UA patients. Compared to clopidogrel combined with the tirofiban group, ticagrelor combined with the tirofiban group had a lower platelet aggregation rate and improved cardiac function of UA patients. Besides, ticagrelor combined with tirofiban group had a better prognosis and the K-M curve showed that UA patients treated by ticagrelor and tirofiban had lower incidences of MACEs in one-year follow-up. The treatment of ticagrelor combined with tirofiban significantly attenuated inflammation response and improved the prognosis of UA patients.

Topics: Aged; Angina, Unstable; Biomarkers; C-Reactive Protein; Clopidogrel; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Kaplan-Meier Estimate; Male; Matrix Metalloproteinase 9; Middle Aged; Platelet Aggregation Inhibitors; Prognosis; Prospective Studies; Ticagrelor; Tirofiban; Tumor Necrosis Factor-alpha

Topics: Humans; Inflammation; Ischemia; Purinergic P2Y Receptor Antagonists; Ticagrelor

Topics: Acute Coronary Syndrome; Adenosine; Cross-Over Studies; Diabetes Mellitus; Endothelial Progenitor Cells; Humans; Inflammation; Prasugrel Hydrochloride; Prospective Studies; Purinergic P2Y Receptor Antagonists; Ticagrelor

Platelet activation and thrombus renewal are keys to intraluminal thrombus formation and progression of abdominal aortic aneurysms (AAA). This study explored the ability of AZD6140, a P2Y(12) receptor antagonist, to inhibit platelet activation and prevent aneurysm development in a rat experimental model of AAA.. Aortic aneurysms were induced by implanting a segment of sodium dodecyl sulfate-decellularized guinea pig aorta in rat aortas. One day later, rats were randomized to AZD6140 (10 mg/kg twice daily by mouth) or diluent (n = 23 per group) for either 10 (n = 18) or 42 days (n = 28). Adenosine diphosphate (ADP)-mediated platelet aggregation, aneurysm expansion, intraluminal thrombus formation, inflammatory infiltration, matrix metalloproteinase-9 (MMP-9) expression, and smooth muscle cell colonization were measured.. AZD6140 inhibited ADP-induced platelet aggregation in vivo for 12 hours, justifying twice-daily administration in rats. The spontaneous increase in aortic diameter shown in the aneurysmal model (2.22 +/- 0.56 mm at day 10 vs 5.21 +/- 1.22 mm at day 42) was reduced with AZD6140 (3.61 +/- 1.46 mm at day 42, P < .01). This beneficial effect was associated with a significant reduction of thrombus development, platelet CD41 expression (P < .05), and leukocyte infiltration of the mural thrombus at days 10 and 42 (P < .01). MMP-9 expression correlated with mural thrombus area and was significantly reduced by AZD6140 (P < .05). AZD6140 limited elastic fiber degradation (P < .05) and enhanced progressive colonization of the thrombus by smooth muscle cells at day 42 (P < .01).. These data suggest that inhibition of platelet activation limits intraluminal thrombus biologic activities, thereby impairing aneurysm development.

Topics: Adenosine; Adenosine Diphosphate; Animals; Aorta; Aortic Aneurysm, Abdominal; Blood Platelets; Disease Models, Animal; Disease Progression; Elastic Tissue; Guinea Pigs; Inflammation; Male; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Rats; Rats, Inbred Lew; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Time Factors; Transplantation, Heterologous