ABSTRACT
OBJECTIVE: Arachidonate 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes. VIA-2291 is a potent 5-LO inhibitor, which has been shown to reduce hsCRP and noncalcified coronary plaque volume following an acute coronary syndrome (ACS). We aim to evaluate the effect of VIA-2291 on vascular inflammation compared to placebo using FDG-PET. METHODS: A Phase II, randomized, double-blind, parallel-group study was conducted in 52 patients with recent ACS assigned 1:1 to either 100 mg VIA-2291 or placebo for 24 weeks. The primary outcome was the effect of VIA-2291 relative to placebo on arterial inflammation detected by (18)fluorodeoxyglucose positron emission tomography (FDG-PET) within the index vessel after 24 weeks of daily treatment, compared to baseline. RESULTS: VIA-2291 was relatively well tolerated and was associated with a significant inhibition of the potent chemo-attractant LTB4, with a mean inhibition of activity of 92.8% (p<0.0001) at 6 weeks in the VIA-2291 group, without further significant change in inhibition at 24 weeks. However, for VIA-2291 was not associated with significant difference in inflammation (target-to-background ratio) compared to placebo at 24 weeks or 6 weeks of treatment. Further, VIA-2291 was not associated with a significant reduction in hsCRP from baseline after either 6 or 24 weeks of treatment. CONCLUSIONS: VIA-2291 is well-tolerated and effectively reduces leukotriene production. However, inhibition of 5-LO with VIA-2291 is not associated with significant reductions in vascular inflammation (by FDG-PET) or in blood inflammatory markers. Accordingly, this study does not provide evidence to support a significant anti-inflammatory effect of VIA-2291 in patients with recent ACS.
Subject(s)
Acute Coronary Syndrome/drug therapy , Aortitis/drug therapy , Carotid Artery Diseases/drug therapy , Hydroxyurea/analogs & derivatives , Lipoxygenase Inhibitors/therapeutic use , Vasculitis/drug therapy , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/enzymology , Aged , Aortitis/diagnosis , Aortitis/enzymology , Aortography/methods , Canada , Carotid Artery Diseases/diagnosis , Carotid Artery Diseases/enzymology , Double-Blind Method , Female , Humans , Hydroxyurea/adverse effects , Hydroxyurea/therapeutic use , Lipoxygenase Inhibitors/adverse effects , Male , Middle Aged , Multidetector Computed Tomography , Multimodal Imaging/methods , Positron-Emission Tomography , Predictive Value of Tests , Time Factors , Treatment Outcome , United States , Vasculitis/diagnosis , Vasculitis/enzymologyABSTRACT
BACKGROUND: Production of leukotrienes by 5-lipoxygenase (5-LO) has been linked to unstable atherosclerotic plaques and cardiovascular events. VIA-2291 is a potent 5-LO inhibitor. METHODS AND RESULTS: In a double-blinded study, 191 patients were randomly assigned 3 weeks after an acute coronary syndrome to receive 25, 50, or 100 mg VIA-2291 or placebo daily for 12 weeks. The primary study end point, whole blood stimulated leukotriene LTB4 at trough drug level, was reduced in all VIA-2291 groups (P<0.0001) in a dose-dependent fashion, with approximately 80% inhibition in >90% of patients in the 100-mg group. A significant reduction of urine leukotriene LTE4 was obtained in all dose groups. No serious adverse events were considered related to study drug. A subset of 93 patients who had undergone a 64-slice coronary CT examination at baseline continued on study medication for a total of 24 weeks and underwent a repeat scan. Five of these patients withdrew or were noncompliant and 28 had nonevaluable scans. Among the 60 remaining patients, new coronary plaques were observed in 5 of 18 (27.8%) placebo-treated patients and in 2 of 42 (4.8%) VIA-2291-treated patients (P=0.01). A reduction in noncalcified plaque volume at 24 weeks versus placebo was observed in VIA-2291-treated groups in the 34 of these 60 patients in whom this end point was analyzable (P<0.01). CONCLUSIONS: VIA-2291 reduces leukotriene production at 12 weeks after an acute coronary syndrome. Preliminary data from the CT substudy suggest that such a reduction in leukotriene production may influence atherosclerosis; however, this requires confirmation in a larger study. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00358826.
Subject(s)
Acute Coronary Syndrome/drug therapy , Hydroxyurea/analogs & derivatives , Lipoxygenase Inhibitors/therapeutic use , Acute Coronary Syndrome/diagnostic imaging , Acute Coronary Syndrome/metabolism , Adult , Aged , Aged, 80 and over , Analysis of Variance , Arachidonate 5-Lipoxygenase/drug effects , Arachidonate 5-Lipoxygenase/metabolism , Biomarkers/blood , Biomarkers/urine , C-Reactive Protein/drug effects , Contrast Media , Coronary Angiography/methods , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Hydroxyurea/therapeutic use , Leukotriene B4/blood , Leukotriene E4/urine , Male , Middle Aged , Observer Variation , Prospective Studies , Radiographic Image Enhancement/methods , Tomography, X-Ray Computed/methods , Treatment Outcome , Triiodobenzoic AcidsABSTRACT
T cell immune responses begin within organized lymphoid tissues. The pace, topology, and outcomes of the cellular interactions that underlie these responses have, so far, been inferred from static imaging of sectioned tissue or from studies of cultured cells. Here we report dynamic visualization of antigen-specific T cells interacting with dendritic cells within intact explanted lymph nodes. We observed immunological synapse formation and prolonged interactions between these two cell types, followed by the activation, dissociation, and rapid migration of T cells away from the antigenic stimulus. This high-resolution spatiotemporal analysis provides insight into the nature of cell interactions critical to early immune responses within lymphoid structures.
