A review on the association of thrombus composition with mechanical and radiological imaging characteristics in acute ischemic stroke.

Thrombus composition and mechanical properties significantly impact the ease and outcomes of thrombectomy procedures in patients with acute ischemic stroke. A wide variation exists in the composition of thrombi between patients. If a relationship can be determined between the composition of a thrombus and its mechanical behaviour, as well as between the composition of a thrombus and its radiological imaging characteristics, then there is the potential to personalise thrombectomy treatment based on each individual thrombus.

Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein.

Leveraging Human Genetics to Estimate Clinical Risk Reductions Achievable by Inhibiting Factor XI.

Background and Purpose- Coagulation factor XI (FXI) is a novel target for antithrombotic therapy addressed by various therapeutic modalities currently in clinical development. The expected magnitude of thrombotic event reduction mediated by targeting FXI is unclear. Methods- We analyzed the association of 2 common genetic variants, which alter levels of FXI, with a range of human phenotypes.

Gradual increase in thrombogenicity of juvenile platelets formed upon offset of prasugrel medication.

In patients with acute coronary syndrome, dual antiplatelet therapy with aspirin and a P2Y12 inhibitor like prasugrel is prescribed for one year. Here, we investigated how the hemostatic function of platelets recovers after discontinuation of prasugrel treatment. Therefore, 16 patients who suffered from ST-elevation myocardial infarction were investigated.

Optimization of ketone-based P2Y(12) receptor antagonists as antithrombotic agents: pharmacodynamics and receptor kinetics considerations.

Modification of a series of P2Y12 receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo.

Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1.

Introduction: Studies have shown that ticagrelor has a further adenosine-mediated mechanism of action in addition to its potent inhibition of the P2Y12 receptor, which may explain some of ticagrelor's clinical characteristics. This study aimed to further characterize the adenosine pharmacology of ticagrelor, its major metabolites, and other P2Y12 receptor antagonists.

Methods: Inhibition of nucleoside transporter-mediated [(3)H]adenosine uptake by ticagrelor, its major metabolites, and alternative P2Y12 antagonists was examined in recombinant Madin-Darby canine kidney (MDCK) cells.

Lead optimization of ethyl 6-aminonicotinate acyl sulfonamides as antagonists of the P2Y12 receptor. separation of the antithrombotic effect and bleeding for candidate drug AZD1283.

Synthesis and structure-activity relationships of ethyl 6-aminonicotinate acyl sulfonamides, which are potent antagonists of the P2Y12 receptor, are presented. Shifting from 5-chlorothienyl to benzyl sulfonamides significantly increased the potency in the residual platelet count assay. Evaluation of PK parameters in vivo in dog for six compounds showed a 10-fold higher clearance for the azetidines than for the matched-pair piperidines.

Synthesis, structure-property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y₁₂ receptor.

The present paper describes the development of a new series of P2Y12 receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 μM, aq solubility <0.1 μM, microsomal CLint (HLM) ≥300 μM/min/mg).

Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans.

Objectives: This study was undertaken to determine if ticagrelor augments adenosine-induced coronary blood flow and the sensation of dyspnea in human subjects.

Background: Ticagrelor is a P2Y(12) receptor antagonist that showed superior clinical benefit versus clopidogrel in a phase III trial (PLATO [Platelet Inhibition and Patient Outcomes]). Ticagrelor has been shown to inhibit cell uptake of adenosine and enhance adenosine-mediated hyperemia responses in a dog model.

Evaluation of ticagrelor pharmacodynamic interactions with reversibly binding or non-reversibly binding P2Y(12) antagonists in an ex-vivo canine model.

Introduction: As ticagrelor, clopidogrel and cangrelor therapies may be used in the same clinical setting, their potential pharmacodynamic interactions are of interest. Hence, we investigated possible interactions between these agents in dogs using a variety of switching protocols.

Methods: Six male dogs all received 7 different dosing regimens separated by 1-5week washout periods: cangrelor (1μg/kg/min, intravenous infusion); ticagrelor (0.

Role of newly formed platelets in thrombus formation in rat after clopidogrel treatment: comparison to the reversible binding P2Y₁₂ antagonist ticagrelor.

Platelet P2Y₁₂ receptors play an important role in arterial thrombosis by stimulating thrombus growth. Both irreversibly (clopidogrel) and reversibly binding (ticagrelor, AZD6140) P2Y₁₂ antagonists are clinically used for restricted periods, but possible differences in platelet function recovery after drug cessation have not been investigated. We treated WKY rats with a single, high dose of 200 mg/kg clopidogrel or 40 mg/kg ticagrelor.

Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model.

Aims: A routine secondary pharmacology screen indicated that reversibly binding oral P2Y(12) receptor antagonist ticagrelor could inhibit adenosine uptake in human erythrocytes, suggesting that ticagrelor may potentiate adenosine-mediated responses in vivo. The aim of this study was to further characterize the adenosine uptake inhibition in vitro and study possible physiological consequences of adenosine uptake inhibition by ticagrelor in an anesthetized dog model of coronary blood flow compared to dipyridamole.

Methods And Results: We measured [2-3H]adenosine uptake in purified human erythrocytes and several cell lines in the presence of ticagrelor or the known uptake inhibitor dipyridamole as a comparator.

A novel series of piperazinyl-pyridine ureas as antagonists of the purinergic P2Y12 receptor.

A novel series of P2Y(12) antagonists for development of drugs within the antiplatelet area is presented. The synthesis of the piperazinyl-pyridine urea derivatives and their structure-activity relationships (SAR) are described. Several compounds showed P2Y(12) antagonistic activities in the sub-micromolar range.

Adjunctive treatment with ticagrelor, but not clopidogrel, added to tPA enables sustained coronary artery recanalisation with recovery of myocardium perfusion in a canine coronary thrombosis model.

Reperfusion therapy for myocardial infarction is limited by significant re-occlusion rates and less-than-optimal myocardial tissue perfusion. It was the objective of this study to assess and compare the effect of ticagrelor, the first reversibly binding oral P2Y12 receptor antagonist, with that of clopidogrel, in conjunction with thrombolytic therapy, on platelet aggregation, thrombus formation, and myocardial perfusion in a canine model. Thrombus formation was induced by electrolytic injury and blood flow was measured with a Doppler ultrasonic flowmeter.

Stabilizing role of platelet P2Y(12) receptors in shear-dependent thrombus formation on ruptured plaques.

Background: In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y(12) receptors. However, such models do not predict involvement of P2Y(12) in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques.

Comparison of ticagrelor and thienopyridine P2Y(12) binding characteristics and antithrombotic and bleeding effects in rat and dog models of thrombosis/hemostasis.

Ticagrelor (AZD6140), the first reversibly binding oral P2Y(12) receptor antagonist, blocks adenosine diphosphate (ADP)-induced platelet aggregation via a mode of action distinct from that of thienopyridine antiplatelet agents. The latter must be metabolically activated and binds irreversibly to P2Y(12) for the life of the platelet, precluding restoration of hemostatic function without the generation of new platelets. In in vitro studies comparing binding characteristics of ticagrelor and compound 105, a chemical compound indistinguishable from the active metabolite of prasugrel, ticagrelor exhibited 1) an approximately 100-fold higher affinity for P2Y(12) and rapid achievement of equilibrium (vs no equilibrium reached with compound 105) as assessed by radioligand displacement in a receptor filtration binding assay, 2) 48-fold greater potency in a functional receptor assay using recombinant human P2Y(12), and 3) 63-fold greater potency in inhibiting ADP-induced aggregation in washed human platelets.

Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist.

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y(12) receptor antagonist that blocks ADP-induced platelet aggregation. Unlike thienopyridines, which irreversibly bind to the P2Y(12) receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels. Animal models indicate greater separation between antithrombotic effects and bleeding effects with ticagrelor than with thienopyridines.

Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation.

Background: P2Y(12) plays an important role in regulating platelet aggregation and function. This receptor is the primary target of thienopyridine antiplatelet agents, the active metabolites of which bind irreversibly to the receptor, and of newer agents that can directly and reversibly modulate receptor activity.

Objective: To characterize the receptor biology of the first reversibly binding oral P2Y(12) antagonist, ticagrelor (AZD6140), a member of the new cyclopentyltriazolopyrimidine (CPTP) class currently in phase III development.

Evaluation of platelet function, a method comparison.

Platelet function can be studied using many different methods why it is of interest to understand how data from different assays relate to each other. In the present study we compare two methods suitable for screening purposes with two established although laborious methods, impedance aggregometry and platelet-rich plasma (PRP) aggregation. The alternative assays tested were: (i) exposure of active alphaIIbbeta3, in diluted whole blood and (ii) whole blood aggregation assessed by residual platelet counting.

Preclinical and clinical studies with selective reversible direct P2Y12 antagonists.

An important role for adenosine diphosphate (ADP)-induced platelet activation and aggregation was proposed more than 40 years ago. The clinical use of clopidogrel, a prodrug of an irreversible P2Y (12) antagonist, has further proved the relevance of inhibiting signaling via the platelet-specific P2Y (12) ADP receptor in the prevention of cardiovascular events. Pharmacological studies at AstraZeneca R&D Charnwood have identified direct, selective, and competitive P2Y (12) antagonists, including cangrelor (also known as AR-C69931MX), which is suitable for intravenous administration, and AZD6140, which is suitable for oral administration.

Acute dyspnoea resulting from pulmonary oedema as the first sign of a phaeochromocytoma.

The day after undergoing neck dissection, a 42-year-old woman developed acute dyspnoea due to pulmonary oedema. Measurements with a Swan-Ganz catheter revealed not only cardiac depression but also a greatly increased peripheral vascular resistance: 5,400 dyn x s x cm(-5)/m2. A phaeochromocytoma with acute cardiac failure leading to pulmonary oedema was considered.

PAI-1 inhibition enhances the lysis of the platelet-rich part of arterial-like thrombi formed in vitro. A comparative study using thrombi prepared from rat and human blood.

We studied the effects of PRAP-1, a PAI-1-inhibiting polyclonal antibody, on tissue-type plasminogen activator (t-PA)-induced lysis of arterial-like thrombi prepared in vitro from rat and human blood in a Chandler loop device. The t-PA induced lysis of the thrombus head and tail was studied over 5 h. For thrombi prepared from rat blood, the lysis ratio head:tail was (mean +/- SD): 0.