prasugrel-hydrochloride and Inflammation

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

While platelets have well characterized effects on monocytes, the effect of platelet activation on CD4+ T-cell differentiation and cytokine production is not clear. To examine the effects of platelet T-cell interactions on T-cell phenotype, and whether these interactions were altered by prasugrel, we conducted a randomized, double-blind, placebo-controlled crossover study in healthy subjects. At baseline the addition of platelets to CD4+ T-cells resulted in an increase in the release of pro-inflammatory cytokine IFN-γ (192% increase in IFN-γ levels, p = 0.01) and pro-inflammatory CD4+ phenotypes, (38% and 58% increase in Th1 and Th17 phenotypic markers respectively, p = 0.01) but no change in Tregs. Prasugrel abolished the effects of platelets on CD4+ T-cells with similar levels of pro-inflammatory cytokines and cell numbers to T-cells stimulated. Antiplatelet therapy may provide therapeutic benefit both from direct platelet inhibition and also through indirect effects on immune response development.

Topics: Adult; Blood Platelets; CD4-Positive T-Lymphocytes; Cell Differentiation; Cross-Over Studies; Cytokines; Fibrinolytic Agents; Flow Cytometry; Humans; Inflammation; Middle Aged; Platelet Activation; Prasugrel Hydrochloride; Prospective Studies; Th1 Cells; Th17 Cells; Young Adult

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

The present study examined the effects of prasugrel in a mouse model of thrombosis-induced neointimal hyperplasia. Following carotid artery injury by application of ferric chloride solution, thrombus formation was assessed on Day 1 and neointimal thickening was assessed on Day 21. Single administrations of prasugrel at 0.3-3mg/kg (p.o.) resulted in a dose-related and sustained inhibition of ADP-induced platelet aggregation through 24h. Single and multiple (1 and 3 weeks) administration of prasugrel (3mg/kg loading and 1mg/kg/day maintenance doses) resulted in a marked inhibition of neointimal thickening in the injured artery. In the dose-response study, a single administration of prasugrel at 0.3-3mg/kg (p.o.) dose-relatedly inhibited thrombus formation and neointimal thickening on Days 1 and 21, respectively. The degree of neointimal hyperplasia in the injured artery correlated significantly with the thrombus indices, time to occlusion and patency rate. To explore possible mechanisms of inhibition of neointimal hyperplasia by prasugrel, mRNA expression levels of inflammatory and fibrosis markers were determined in injured arteries. Prasugrel treatment resulted in reduced MCP-1, ICAM-1 and TGF-β mRNA levels on Day 2 (24h after the injury) and Day 8 (1 week after the injury) in the target arteries. In conclusion, we found that a single oral loading dose of prasugrel markedly prevented neointimal hyperplasia by inhibiting platelet activation and thrombus formation and was associated with inhibition of the expression of inflammatory and fibrosis markers, including MCP-1, ICAM-1 and TGF-β, in the injured arteries.

Topics: Adenosine Diphosphate; Animals; Aorta; Arterial Occlusive Diseases; Arteries; Carotid Arteries; Chemokine CCL2; Chlorides; Ferric Compounds; Hyperplasia; Inflammation; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred C57BL; Neointima; Platelet Aggregation; Prasugrel Hydrochloride; Pyridines; RNA, Messenger; Thrombosis; Time Factors; Transforming Growth Factor beta1

Administration of the thienopyridine P2Y12 receptor antagonist, clopidogrel, increased the erosive arthritis induced by peptidoglycan polysaccharide (PG-PS) in rats or by injection of the arthritogenic K/BxN serum in mice. To determine if the detrimental effects are caused exclusively by clopidogrel, we evaluated prasugrel, a third-generation thienopyridine pro-drug, that contrary to clopidogrel is mostly metabolized into its active metabolite in the intestine. Prasugrel effects were examined on the PG-PS-induced arthritis rat model. Erosive arthritis was induced in Lewis rats followed by treatment with prasugrel for 21 days. Prasugrel treated arthritic animals showed a significant increase in the inflammatory response, compared with untreated arthritic rats, in terms of augmented macroscopic joint diameter associated with significant signs of inflammation, histomorphometric measurements of the hind joints and elevated platelet number. Moreover, fibrosis at the pannus, assessed by immunofluorescence of connective tissue growth factor, was increased in arthritic rats treated with prasugrel. In addition to the arthritic manifestations, hepatomegaly, liver granulomas and giant cell formation were observed after PG-PS induction and even more after prasugrel exposure. Cytokine plasma levels of IL-1 beta, IL-6, MIP1 alpha, MCP1, IL-17 and RANTES were increased in arthritis-induced animals. IL-10 plasma levels were significantly decreased in animals treated with prasugrel. Overall, prasugrel enhances inflammation in joints and liver of this animal model. Since prasugrel metabolites inhibit neutrophil function ex-vivo and the effects of both clopidogrel and prasugrel metabolites on platelets are identical, we conclude that the thienopyridines metabolites might exert non-platelet effects on other immune cells to aggravate inflammation.

Topics: Animals; Arthritis, Experimental; Clopidogrel; Cytokines; Female; Granuloma; Inflammation; Joints; Liver; Peptidoglycan; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prodrugs; Rats; Rats, Inbred Lew; Thiophenes; Ticlopidine

Clopidogrel and prasugrel belong to a thienopyridine class of oral antiplatelet drugs that, after having been metabolized in the liver, can inhibit platelet function by irreversibly antagonizing the P2Y(12) receptor. Furthermore, thienopyridines influence numerous inflammatory conditions, but their effects on neutrophils have not been evaluated, despite the important role of these cells in inflammation. Therefore, we investigated the effect of prasugrel metabolites on neutrophils to further clarify the role of thienopyridines in inflammation. Interestingly, a prasugrel metabolite mixture, produced in vitro using rat liver microsomes, significantly inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP)- and platelet-activating factor (PAF)-induced neutrophil activation. More specifically, prasugrel metabolites inhibited neutrophil transmigration, CD16 surface expression, and neutrophil-platelet aggregation. Moreover, prasugrel metabolite pretreatment also significantly decreased fMLP- or PAF-induced extracellular-signal-regulated kinase phosphorylation as well as calcium mobilization. To determine the target of prasugrel in neutrophils, the role of both P2Y(12) and P2Y(13) receptors was studied using specific reversible antagonists, AR-C69931MX and MRS2211, respectively. Neither antagonist had any direct effect on the agonist-induced neutrophil functional responses. Our findings indicate that prasugrel metabolites may directly target neutrophils and inhibit their activation, suggesting a possible explanation for their anti-inflammatory effects previously observed. However, these metabolites do not act through either the P2Y(12) or P2Y(13) receptor in neutrophils.

Topics: Animals; Blotting, Western; Calcium; CD11b Antigen; Cell Separation; Cell Survival; Chemotaxis, Leukocyte; Humans; Inflammation; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Microsomes, Liver; Neutrophils; Peroxidase; Piperazines; Platelet Aggregation; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thiophenes

The novel thienopyridine prodrug prasugrel, a platelet P2Y(12) ADP receptor antagonist, requires in vivo metabolism for activity. Although pharmacological data have been collected on the effects of prasugrel on platelet aggregation, there are few data on the direct effects of the prasugrel's active metabolite, R-138727, on other aspects of platelet function. Here we examined the effects of R-138727 on thrombo-inflammatory markers of platelet activation, and the possible modulatory effects of other blood cells, calcium, and aspirin. Blood (PPACK or citrate anticoagulated) from healthy donors pre- and post-aspirin was incubated with R-138727 and the response to ADP assessed in whole blood or platelet-rich plasma (PRP) by aggregometry and flow cytometric analysis of leukocyte-platelet aggregates, platelet surface P-selectin, and GPIIb-IIIa activation. Low-micromolar concentrations of R-138727 resulted in a rapid and consistent inhibition of these ADP-stimulated thrombo-inflammatory markers. These rapid kinetics required physiological calcium levels, but were largely unaffected by aspirin. Lower IC(50) values in whole blood relative to PRP suggested that other blood cells affect ADP-induced platelet activation and hence the net inhibition by R-138727. R-138727 did not inhibit P2Y(12)-mediated ADP-induced shape change, even at concentrations that completely inhibited platelet aggregation, confirming the specificity of R-138727 for P2Y(12). In conclusion, R-138727, the active metabolite of prasugrel, results in rapid, potent, consistent, and selective inhibition of P2Y(12)-mediated up-regulation of thrombo-inflammatory markers of platelet activation. This inhibition is enhanced in the presence other blood cells and calcium, but not aspirin.

Topics: Adenosine Diphosphate; Adult; Aspirin; Biomarkers; Blood Cells; Calcium; Cells, Cultured; Female; Humans; Inflammation; Kinetics; Male; Middle Aged; Piperazines; Platelet Activation; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Thiophenes; Thrombosis; Up-Regulation