Endothelial Function in Systemic Lupus Erythematosus: Relationship to Disease Activity, Cardiovascular Risk Factors, Corticosteroid Therapy, and Coronary Calcification

Elizabeth Turner2, Victor Dishy1, Cecilia P Chung2, Paul Harris4, Rosanna Pierce5, Yu Asanuma1, Annette Oeser1, Tebeb Gebretsadik3, Ayumi Shintani3, Paolo Raggi6, C Michael Stein1,21Division of Clinical Pharmacology, 2Division of Rheumatology, 3Department of Medicine; Center of Health Services Research, Department of Biostatistics; 4General Clinical Research Center; 5Department of Vascular Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA; 6Section of Cardiology, Tulane University School of Medicine, New Orleans, LA, USAObjectives: Endothelial dysfunction is frequently present in patients with systemic lupus erythematosus and may increase their risk of premature coronary artery disease. In this pilot study we have characterized the relationship between endothelial function, measures of disease activity, and cardiovascular risk factors in patients with lupus.Methods: Clinical characteristics and cardiovascular risk factors were evaluated in 20 patients with lupus. Flow-mediated dilation of the brachial artery was measured using high resolution ultrasound and the presence or absence of coronary calcification determined by electronbeam computed tomography. The relationship between these variables and flow-mediated dilation was determined using Spearman correlation coefficients (RHO) and Mann Whitney-Wilcoxon tests.Results: Twenty patients (17 female) median age (interquartile range) 42.5 (32.0–47.5) years were studied. The median flow-mediated vasodilation was 3.6% (1.7%–7.7%). In patients with coronary calcification (n = 6), flow-mediated dilation was 2.1% (–0.42%–3.6%) compared with 4.0% (3.5%–8.3%) in those without (p = 0.12). There was no significant relationship between flow-mediated dilation and markers of disease activity, duration of disease, and cardiovascular risk factors. Lower flow-mediated dilation was associated with duration of corticosteroid therapy (RHO = –0.44, p = 0.05).Conclusions: In these preliminary results, endothelial dysfunction is associated with longterm exposure to corticosteroids.Keywords: flow-mediated dilation, endothelium, inflammation, atherosclerosis, systemic lupus erythematosu

The effects of laropiprant, a selective prostaglandin D₂ receptor 1 antagonist, on the antiplatelet activity of clopidogrel or aspirin.

Laropiprant (LRPT) is being developed in combination with Merck\u27s extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD₂ receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A₂ receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady-state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time at 24 h post-dose (trough) was pre-specified as the primary pharmacodynamic endpoint in both studies. Two separate, double-blind, randomized, placebo-controlled, crossover studies evaluated the effects of multiple-dose LRPT on the pharmacodynamics of multiple-dose clopidogrel or aspirin. Healthy subjects were randomized to once-daily oral doses of LRPT 40 mg or placebo to LRTP co-administered with clopidogrel 75 mg or aspirin 81 mg for 7 days with at least a 21-day washout between treatments. In both studies, bleeding time and platelet aggregation were assessed 4 and 24 hours post-dose on Day 7. Comparability was declared if the 90% confidence interval for the estimated geometric mean ratio ([LRPT+clopidogrel]/clopidogrel alone or [LRPT+aspirin]/aspirin alone) for bleeding time at 24 hours post-dose on Day 7 was contained within (0.66, 1.50). Concomitant daily administration of LRPT 40 mg with clopidogrel 75 mg or aspirin 81 mg resulted in an approximate 4-5% increase in bleeding time at 24 hours after the last dose vs. bleeding time after treatment with clopidogrel or aspirin alone, demonstrating that the treatments had comparable effects on bleeding time. Percent inhibition of platelet aggregation was not significantly different between LRPT co-administered with clopidogrel or aspirin vs. clopidogrel or aspirin alone at 24 hours post-dose at steady state. At 4 hours after the last dose, co-administration of LRPT 40 mg resulted in 3% and 41% increase in bleeding time vs. bleeding time after treatment with aspirin or clopidogrel alone, respectively. Co-administration of LPRT with clopidogrel or aspirin was generally well tolerated in healthy subjects. Co-administration of multiple doses of LRPT 40 mg and clopidogrel 75 mg or aspirin 81 mg had no clinically important effects on bleeding time or platelet aggregation