The Relationship Between Uric Acid and Inflammatory Markers
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Uric acid is a substance found in the blood that may contribute to certain chronic medical
      conditions and disorders, such as diabetes, insulin resistance, and high blood pressure. High
      uric acid concentrations have been associated with stroke and heart disease, as well as
      chronic heart failure. In particular, researchers are interested in determining the
      relationship between uric acid and inflammatory markers, or chemicals in the blood that can
      indicate inflammation and other problems with the body.

      Objectives:

        -  To study the specific effects of changes in uric acid in the body.

        -  To determine whether uric acid contributes to inflammation in the body.

      Eligibility:

      - Healthy individuals between 50 and 75 years of age.

      Design:

        -  This study will involve four visits: a screening visit, two study visits, and a followup
           visit.

        -  At the screening visit, participants will have a physical examination, blood and urine
           tests, and an electrocardiogram. Participants will be divided into two groups based on
           the existing amount of uric acid in their blood.

        -  Within 7 days of the screening visit, participants will have a full-day study visit with
           a magnetic resonance imaging scan, followed by a high-fat meal and further blood samples
           collected over the following 8 hours.

        -  At least 2 days after the first study visit, participants will have the second study
           visit, which will require a 2-night stay at the National Institutes of Health.
           Participants will have a metabolism test, and will receive the following infusions based
           on the groups they were assigned to at the screening visit.

        -  Group A (low uric acid) will receive either uric acid or a placebo.

        -  Group B (moderate to high uric acid) will receive either Rasburicase (a drug that
           reduces the amount of uric acid in the blood) or a placebo.

        -  After the infusions and related blood tests, participants will have a high-fat meal with
           further blood and urine samples.

        -  Approximately 2 weeks after the second study visit, participants will have a final
           followup visit with additional blood and urine tests to determine whether the levels of
           uric acid in the blood have returned to normal.
    

Detailed description: 
      Uric acid (UA) is a terminal product of purine metabolism with strong antioxidant properties.
      UA has sizeable concentrations in biologic fluids only in humans and primates because they
      have a non-functional mutation of the enzyme uricase that, in other animals, transforms UA to
      allantoin. It has been hypothesized that this mutation has emerged evolutionarily because
      through this mechanism, humans can counteract the excessive oxidative stress that occurs in
      many critical pathologic conditions. Partially in contrast with this theory, high levels of
      UA have been associated with a number of negative health outcomes, including cardiovascular
      as well as all-cause mortality. Although it is possible that the UA elevation is merely a
      marker of critical health because it is an inducible antioxidant, researchers have questioned
      whether UA has beneficial or detrimental effect on health status. For example, we recently
      demonstrated that higher UA levels are cross-sectionally associated with higher levels of
      pro-inflammatory markers, and predict the increase in inflammatory markers over a 3-year
      follow-up. Understanding whether UA exerts a protective or detrimental effect on health is
      important in deciding whether mild hyperuricemia should or should not be aggressively
      treated.

      Unfortunately, observational studies cannot fully address this question. In fact, we cannot
      exclude that the cross-sectional and longitudinal association between UA, inflammatory
      markers and negative health outcomes, may simply reflect the fact that UA is an inducible
      antioxidant that is produced in response to increasing oxidative stress. To verify the
      hypothesis that UA activates inflammation, we plan to conduct two complementary randomized
      controlled trials, each one including 10 treated and 10 control subjects. In the first
      trials, subjects with low UA will be administered 500 mg of UA intravenously. In the second
      trials, subjects with moderately elevated UA will be administered a single acute dose of
      Rasburicase. Then inflammatory markers will be measured at multiple points in time, for a
      total of 32 hours. We hypothesize that an acute increase in the circulating levels of UA will
      be followed by increasing levels of inflammatory markers. At the same time, an acute
      reduction of UA levels will be followed by a progressive reduction of inflammatory markers.
      This study should provide information that will help clinicians to decide whether to or not
      to treat mild hyperuricemia.
    

Intervention name(s): IV Uric Acid; IV Rasburicase
Intervention type(s): Drug; Drug
Intervention MeSH terms: Rasburicase; Uric Acid
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Uric Acid; Rasburicase; Inflammatory Markers