E5555 is a potent protease-activated receptor (PAR-1) antagonist targeting the G-coupled receptor and modulating thrombin-platelet-endothelial interactions. The drug is currently being tested in phase II trials in patients with coronary artery disease (CAD) and has potential antithrombotic and anti-inflammatory benefits. We investigated the in-vitro effects of E5555 on platelet function beyond PAR-1 blockade in healthy volunteers and CAD patients treated with aspirin (ASA) with or without clopidogrel. Conventional aggregation induced by 5 microM ADP, 1 microg/ml collagen, 10 microM TRAP, whole blood aggregation with 1 microg/ml collagen, and expression of 14 intact, and TRAP-stimulated receptors by flow cytometry were utilised to assess platelet activity after preincubation with escalating concentrations of E5555 (20 ng/ml, 50 ng/ml, and 100 ng/ml) in healthy volunteers, CAD patients treated with ASA, and CAD patients treated with ASA and clopidogrel combination (n=10, for each group). E5555 inhibited a number of platelet biomarkers. Platelet inhibition was usually moderate, present already at 20 ng/ml, and was not seemingly dose-dependent without TRAP stimulation. E5555 caused 10-15% inhibition of ADP- and collagen-induced platelet aggregation in plasma, but not in whole blood. TRAP-induced aggregation was inhibited almost completely. PECAM-I, GP IIb/IIIa antigen, and activity with PAC-1, GPIb, thrombospondin, vitronectin receptor expression, and formation of platelet-monocyte aggregates were also significantly reduced by E5555. TRAP stimulation caused dose-dependent effects between 20 and 50 ng/ml E5555 doses. P-selectin, LAMP-1, LAMP, and CD40-ligand were not affected by E5555. In conclusion, E5555 in vitro moderately but significantly inhibits platelet activity beyond PAR-1 blockade. Antiplatelet potency of ASA alone, and the combination of ASA and clopidogrel may be enhanced by E5555 providing rationale for their synergistic use. Selective blockade of platelet receptors suggests unique antiplatelet properties of E5555 as a potential addition to current antithrombotic regimens.
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http://dx.doi.org/10.1160/TH08-12-0805 | DOI Listing |
Cell Mol Gastroenterol Hepatol
June 2024
Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
Background & Aims: Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR antagonism on colitis-associated carcinogenesis.
View Article and Find Full Text PDFPlast Reconstr Surg Glob Open
January 2024
Private Practice, Lima, Peru.
Background: This study aimed to identify and describe indicators of depression, anxiety, body dissatisfaction, and risk of an eating disorder in patients who undergo plastic surgery.
Methods: The sample was made up of 90 patients from a private clinic in Lima, Peru, with ages between 20 and 50 years. The participants were asked to answer the Aaron Beck Depression Inventory (BDI-II), the Aaron Beck Anxiety Inventory, the Body Shape Questionnaire, and the Abbreviated and Modified Eating Attitudes Scale (EAT - 26M).
Biomed Chromatogr
July 2023
Department of Chemistry, University of Turin, Italy.
The purpose of this review study was to sum up the main recent advances reported in the scientific literature about the detection of common drugs of abuse in biological samples upon their collection by dried blood spot devices. The most recent, innovative and fully validated methods for the qualitative and/or quantitative detection of common drugs of abuse are reported, including alprazolam, clonazepam, diazepam, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methyl-enedioxyethylamphetamine, amphetamine, methamphetamine, cocaine, tetrahydrocannabinol, 6-monoacetylmorphine, morphine, codeine, hydromorphone, hydrocodone, oxycodone, noroxycodone, tramadol, methadone, buprenorphine, fentanyl, ketamine and their respective metabolites and γ-hydroxybutyric acid. Dried blood spot proved to be extremely promising for routine analysis of forensic cases, although large-scale experiments on real samples need to be performed to confirm the emerging advantages of the technique and remove the potential limitations still affecting its widespread application.
View Article and Find Full Text PDFAm J Physiol Renal Physiol
May 2020
Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences and Faculty of Pharmaceutical Sciences, Sendai, Japan.
Protease-activated receptors (PARs) are coagulation protease targets, and they increase expression of inflammatory cytokines and chemokines in various diseases. Of all PARs, previous reports have shown that PAR1 or PAR2 inhibition is protective against diabetic glomerular injury. However, how PAR1 and PAR2 cooperatively contribute to diabetic kidney disease (DKD) pathogenesis and whether dual blockade of PARs is more effective in DKD remain elusive.
View Article and Find Full Text PDFCureus
September 2019
Ophthalmology / Neuro-Ophthalmology, University of Turin, Turin, ITA.
Introduction Early diagnosis is the main requisite when dealing with subjects suspected to suffer from neurodevelopmental disorders, especially reading disability. In this respect, self-reports are a promising tool and could prove to be as reliable as ordinary screenings, with the advantage of low cost and low time consumption. Since the last decades, the perceptual and visuomotor function are believed to be involved in the pathogenesis of developmental dyslexia; therefore, specific elements related to an alteration of the sensorial and visuomotor domain in the familial and personal medical history could reveal a risk to develop this condition at a pre-examination phase.
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