3 research outputs found
Functionalized porous silica&maghemite core-shell nanoparticles for applications in medicine: design, synthesis, and immunotoxicity
Aim To determine cytotoxicity and effect of silica-coated
magnetic nanoparticles (MNPs) on immune response, in
particular lymphocyte proliferative activity, phagocytic activity,
and leukocyte respiratory burst and in vitro production
of interleukin-6 (IL-6) and 8 (IL-8), interferon-gamma
(IFN-γ), tumor necrosis factor-alpha (TNF-α), and granulocyte
macrophage colony stimulating factor (GM-CSF).
Methods Maghemite was prepared by coprecipitation of
iron salts with ammonia, oxidation with NaOCl and modified
by tetramethyl orthosilicate and aminosilanes. Particles
were characterized by transmission electron microscopy
(TEM), dynamic light scattering (DLS), Fourier-transform infrared
(FTIR), and X-ray photoelectron spectroscopy (XPS).
Cytotoxicity and lymphocyte proliferative activity were
assessed using [3H]-thymidine incorporation into DNA of
proliferating human peripheral blood cells. Phagocytic activity
and leukocyte respiratory burst were measured by
flow cytometry; cytokine levels in cell supernatants were
determined by ELISA.
Results γ-Fe2O3&SiO2-NH2 MNPs were 13 nm in size. According
to TEM, they were localized in the cell cytoplasm
and extracellular space. Neither cytotoxic effect nor significant
differences in T-lymphocyte and T-dependent Bcell
proliferative response were found at particle concentrations
0.12-75 μg/cm2 after 24, 48, and 72 h incubation.
Significantly increased production of IL-6 and 8, and GMCSF
cytokines was observed in the cells treated with 3, 15,
and 75 μg of particles/cm2 for 48 h and stimulated with
pokeweed mitogen (PHA). No significant changes in TNF-α
and IFN-γ production were observed. MNPs did not affect
phagocytic activity of monocytes and granulocytes when
added to cells for 24 and 48 h. Phagocytic respiratory burst
was significantly enhanced in the cultures exposed to 75
μg MNPs/cm2 for 48 h.
Conclusions The cytotoxicity and in vitro immunotoxicity
were found to be minimal in the newly developed porous
core-shell γ-Fe2O3&SiO2-NH2 magnetic nanoparticles
Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease
BACKGROUND:
The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease.
METHODS:
In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.
RESULTS:
At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91).
CONCLUSIONS:
Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)