Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Hydrogen-bonded networks: (phosphine)gold(I) 4-amino-2-pyrimidine-thiolates

Wilton-Ely JDET, Schier A, Mitzel NW, Nogai S, Schmidbaur H. Hydrogen-bonded networks: (phosphine)gold(I) 4-amino-2-pyrimidine-thiolates. JOURNAL OF ORGANOMETALLIC CHEMISTRY. 2002;643-644:313-323.Treatment of the gold(I) halide complexes LAuCl (where L = PMe3, PEt3, PPh3, PPh2Py) and PP(AuCl)(2) [where PP = bis(diphenylphosphino)methane 1,1'-bis(diphenylphosphino)ferrocene] with 4-amino-2-pvrimidine-thiol (2-SPym-4-NH2) (one or two equivalents as required) in the presence of sodium methoxide provides the corresponding (phosphine)gold(I) thiolate complexes LAu(2-SPym-4-NH2) and PP[Au(2-SPym-4-NH2)](2), respectively. A polyaurated product [(Ph3PAu)(2)(2-SPym-4-NH2)]BF4 is obtained on treating the thiol with the oxonium complex [(Ph3PAu)(3)O]BF4. The compounds LAu(2-SPym-4-NH2) (L = PPh3, PPh2Py, PEt3) and [(dppm)Au-2(2-SPym-4-NH2)(2)] have been investigated crystallographically. (C) 2002 Elsevier Science B.V. All rights reserved

Cluster self-assembly of di[gold(I)]halonium cations

Treatment of gold(I) halide complexes of the type L-Au-X [where L = PPh(3), PEt(3) with X = Cl, Br, I, or L = 2,6-(MeO)(2)C(6)H(3)PPh(2) with X = Cl] with AgSbF(6) in the molar ratio 2:1 in dichloromethane/tetrahydrofuran at −78°C affords high yields of di[gold(I)]halonium salts of the formula {X[Au(PR(3))](2)}(+) SbF [Formula: see text] (2-8). A determination of the crystal structures of the four triarylphosphine complexes (2-4, 8) revealed the presence of novel tetranuclear dications with a highly symmetrical structure (point group S(4)) that arises from self-assembly of the dinuclear monocations through a set of four equivalent aurophilic Au–Au interactions. A comparison with two reference structures of corresponding chloronium perchlorate and bromonium tetrafluoroborate salts with monomeric, dinuclear cations shows that the geometry of the latter is greatly altered on dimerization to optimize the interactions between the closed-shell metal centers (Au: 5d(10)). Weak metallophilic bonding clearly becomes significant only in crystal lattices where anions with a larger ionic radius (SbF [Formula: see text] vs. BF [Formula: see text] , ClO [Formula: see text]) reduce the otherwise dominant role of strong interionic Coulomb forces. The results indicate that aurophilic bonding is indeed an ubiquitous, quite dependable mode of intermetallic interactions provided that the right environment is chosen to allow the weak forces to become operative

MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease

BACKGROUND: The bacterial microflora aggravates graft-versus-host-disease (GvHD) after allogeneic stem cell transplantation, but the underlying mechanisms of manifestations of intestinal GvHD (iGvHD) in the gut remain poorly understood. AIM: To analyse the gut flora composition and the impact of bacterial sensing via Toll-like receptors (TLRs) in iGvHD. METHODS: By mimicking clinical low-intensity conditioning regimens used in humans, a novel irradiation independent, treosulfan and cyclophosphamide-based murine allogeneic transplantation model was established. A global survey of the intestinal microflora by cultural and molecular methods was performed, the intestinal immunopathology in TLR-deficient recipient mice with iGvHD investigated and finally, the impact of anti-TLR9 treatment on iGvHD development assessed. RESULTS: The inflammatory responses in iGvHD were accompanied by gut flora shifts towards enterobacteria, enterococci and Bacteroides/Prevotella spp. Analysis of iGvHD in MyD88-/-, TRIF-/-, TLR2/4-/-, and TLR9-/- recipient mice showed that bacterial sensing via TLRs was essential for iGvHD development. Acute iGvHD was characterised by increasing numbers of apoptotic cells, proliferating cells, T cells and neutrophils within the colon. These responses were significantly reduced in MyD88-/-, TLR2/4-/-, TRIF-/- and TLR9-/- mice, as compared with wild-type controls. However, TRIF-/- and TLR2/4-/- mice were not protected from mortality, whereas TLR9-/- mice displayed increased survival rates. The important role of TLR9-mediated immunopathology was independently confirmed by significantly reduced macroscopic disease symptoms and colonic apoptosis as well as by reduced T-cell and neutrophil numbers within the colon after treatment with a synthetic inhibitory oligonucleotide. CONCLUSIONS: These results emphasise the critical role of gut microbiota, innate immunity and TLR9 in iGvHD and highlight anti-TLR9 strategies as novel therapeutic options