Testing treatments causing opposite change of circulating UA levels is the only approach that can shed light on whether UA is a causal, compensatory or co-incidental factor associated with modification of the inflammatory status. In the Cohort#1: Uric Acid versus Placebo Trial, UA systemic infusion will rapidly increase the circulating UA levels. We expect that the sudden increase of circulating UA levels may directly affect circulating levels of cytokines, antioxidant biomarkers and other outcome parameters. In the Cohort#2: Rasburicase versus Placebo Trial, Rasburicase systemic administration will rapidly lower the circulating UA levels without restoration of them within few days from the infusion. We expect that a sudden decrease of circulating UA levels may affect circulating cytokines, antioxidant biomarkers and all other outcomes with an opposite fashion compared to Cohort#1. Both short term approaches of Cohort#1: Uric Acid versus Placebo Trial and Cohort#2: Rasburicase versus Placebo Trial are more likely to allow a better understanding of the possible mechanisms that link raised circulating UA levels and increased cardiovascular risk that observational and epidemiological data are unlikely to resolve. Additionally, this would be a valid approach in healthy individuals as suggested by studies exploring the effect of sudden changes of cardiovascular risk factors, such as saturated fats or circulating homocysteine concentrations, on biological and instrumental parameters (33, 34). Study Design Twenty (10m,10f) participants with UA <6mg/dl will be enrolled in Cohort#1, while 20 (10m, 10f) participants with UA >7mg/dl will be enrolled in Cohort#2. All participants must be capable of attending an outpatient setting at the required protocol time-points. All participants will be evaluated frequently for 24h during the active part of the study. The long-term effect will be evaluated at visit 4 and visit 5 that will be scheduled at 48 hours and 2 weeks from treatment, respectively. In all, 32 participants have been enrolled.
