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.

DPPH radical scavenging activity of several naturally occurring coumarins and their synthesized analogs measured by the SIA method

ABSTRACT Coumarins, naturally occurring compounds derived from benzopyran, have recently been studied extensively for their antioxidant properties. A lot of coumarins have been isolated and identified from natural sources and many others have been synthesized. It is also known that pharmacological and biochemical properties and thus also therapeutic application of simple coumarins depend upon the pattern of their substitution. As a part of studies of biological effects, four naturally occurring coumarins and 18 synthesized analogs of several compounds were assayed for 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging activity. For this purpose the highly reliable DPPH test modified to be performed by sequential injection analysis (SIA) system was used. This in our laboratory-developed method was originally proposed for antioxidant screening of large series of plant extracts. In this assay, the DPPH test using the SIA method was used for fast and sensitive evaluation of EC(50) of coumarins. The evaluation of EC(50) of a single compound takes only 15 to 30 min. The structure-activity relationships of tested compounds are also established. The results verified 7,8-dihydroxy-4-methylcoumarins as excellent DPPH radical scavengers. Obtained results correspond with those of other studies and suggest the SIA procedure as a suitable method for fast and sensitive antioxidant analysis of various types of compounds