Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Lipid peroxidation and its control in Anguilla anguilla hepatocytes under silica-coated iron oxide nanoparticles (with or without mercury) exposure

Having multidisciplinary applications, iron oxide nanoparticles can inevitably enter aquatic system and impact inhabitants such as fish. However, the studies in this context have ignored the significance of obvious interaction of iron oxide nanoparticles with other persistent co-contaminants such as mercury (Hg) in the modulation of the toxicity and underlying mechanisms of iron oxide nanoparticles and Hg alone, and concomitant exposures. This study aimed to evaluate lipid peroxidation (LPO) and its control with glutathione (GSH) and associated enzymes (such as glutathione reductase, GR; glutathione peroxidase, GPX; glutathione sulfo-transferase, GST) in European eel (Anguilla anguilla L.) hepatocytes exposed to stressors with following schemes: (i) no silica-coated iron oxide nanoparticles functionalized with dithiocarbamate (Fe3O4@SiO2/Si DTC, hereafter called 'FeNPs'; size range 82 +/- 21 to 100 +/- 30 nm) or Hg, (ii) FeNPs (2.5 mu g L-1) alone, (iii) Hg (50 mu g L-1) alone and (iv) FeNPs + Hg concomitant condition during 0 to 72 h. The exhibition of a differential coordination between GSH regeneration (determined as GR activity) and GSH metabolism (determined as the activity of GPX and GST) was perceptible in A. anguilla hepatocytes in order to control FeNPs, Hg and FeNPs + Hg exposure condition-mediated LPO. This study revealed the significance of a fine tuning among GR, GPX and GST in keeping LPO level under control during FeNPs or Hg alone exposure, and a direct role of total GSH (TGSH) in the control of LPO level and impaired GSH metabolism under the concomitant (FeNPs + Hg) exposure. An interpretation of the fish risk to FeNPs in a multi-pollution state should equally consider the potential outcome of the interaction of FeNPs with other contaminants