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.

Synthesis and Characterization of a Linear Dinitrosyl-Triiron Complex

Nitric oxide is released during the immune response by the host during bacterial infection. To counteract this response, bacteria have evolved nitric oxide reductases to convert NO to N[subscript 2]O. Some of these nitric oxide reductases contain a flavodiiron active site that has bridging carboxylates and hydroxides. Only a handful of synthetic complexes currently exist as models for the protein reactivity. Here, we report the reaction of [Fe[subscript 2](μ-OH)(μ-Ph[subscript 4]DBA)(TMEDA)[subscript 2](OTf)] (4) with NO(g) and Ph[subscript 3]CSNO to prepare the dinitrosyl-triiron complex [Fe[subscript 3](μ-OH)[subscript 2](μ-Ph[subscript 4]DBA)[subscript 2](TMEDA)[subscript 2](NO)[subscript 2]](OTf) (5). The reaction was monitored by UV/Vis and ReactIR spectroscopy, and compound 5 was characterized by X-ray crystallography, [superscript 57]Fe Mossbauer spectroscopy, Evan's method, and FTIR spectroscopy. The IR spectrum of compound 5 compares favorably to experimental spectroscopic data obtained for the proposed mononitrosylated intermediate of the protein.National Science Foundation (U.S.) (Grant CHE0907905