ABSTRACT
BACKGROUND: Platelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of P-selectin on activated platelets induces formation of platelet-monocyte aggregates and promotes vascular inflammation and thrombosis. P-selectin antagonism may represent a novel therapeutic strategy in vascular disease. We aimed to investigate the effects of the novel P-selectin antagonist PSI-697 on platelet-monocyte aggregate formation in humans. METHODS AND RESULTS: In a double-blind, randomized, placebo-controlled crossover study, healthy smokers were randomized to receive either oral PSI-697 600 mg or matched placebo. The sequence of treatment was also randomized, with all subjects receiving both PSI-697 and placebo. Platelet-monocyte aggregates were measured by flow cytometry at 4 and 24 hours in the presence and absence of thrombin receptor-activating peptide (TRAP; 0.1 to 1.0 µm/L). The ex vivo addition of TRAP caused a concentration-dependent increase in platelet-monocyte aggregates from 8.2% to 94.8% (P<0.001). At 4 and 24 hours, plasma concentrations of PSI-697 increased to 1906 and 83 ng/mL, respectively (P<0.001). PSI-697 had no demonstrable effect on either stimulated or unstimulated platelet-monocyte aggregates at 4 or 24 hours (P>0.05). P-selectin-blocking antibody (CLB-Thromb6), but not PSI-697, inhibited both stimulated and unstimulated platelet-monocyte aggregate formation in vitro (P<0.001). CONCLUSIONS: The novel small-molecule P-selectin antagonist PSI-697 did not inhibit basal or stimulated platelet-monocyte aggregate formation in humans at the dose tested. Its clinical efficacy remains to be established. CLINICAL TRIAL REGISTRATION: URL: http://EudraCT.ema.europa.eu Unique identifier: 2007-005695-14.
Subject(s)
Blood Platelets/drug effects , Hydroxyquinolines/administration & dosage , Monocytes/drug effects , Platelet Adhesiveness/drug effects , Platelet Aggregation Inhibitors/administration & dosage , Selenoprotein P/antagonists & inhibitors , Smoking/blood , Administration, Oral , Blood Platelets/metabolism , Cross-Over Studies , Double-Blind Method , Flow Cytometry , Humans , Monocytes/metabolism , Platelet Function Tests , Scotland , Selenoprotein P/blood , Time FactorsABSTRACT
INTRODUCTION: The management and risk stratification of patients with syncope in the Emergency Department (ED) has been the emphasis of much recent research, however little is known about inpatient management especially in the UK. The aim of this study was to examine the inpatient management of patients with syncope admitted to hospital from a UK ED. METHODS: This was a single centre prospective observational cohort study, recruiting patients with syncope admitted to hospital from a UK ED. Inpatient management was examined focusing on length of stay and investigations undertaken. RESULTS: Between 3 March 2007 and 22 July 2008, 540 patients presenting with syncope to the ED of the Royal Infirmary of Edinburgh, UK were admitted and enrolled. Median and mean length of stay was 1 day (IQR 1-4) and 6.3 days (SD 15.5). In all, 392 (73%) patients were admitted to General/Acute Medicine, 39 (7%) to Cardiology, 35 (7%) to Medicine of the Elderly, 33 (6%) to surgical specialities and the rest to other specialities. A diagnosis was finally made in 342 (63%) patients including 33 (85%) of the 39 admitted to Cardiology and 239 (61%) of the 392 patients admitted to General/Acute Medicine. The use of diagnostic tests varied between specialities with more intensive investigation undertaken in patients admitted to Cardiology. CONCLUSIONS: The current approach to the inpatient management of syncope is speciality dependent. Standardised diagnostic pathways may improve diagnostic yield and cost effectiveness.
