Inosine to Increase Serum and Cerebrospinal Fluid Urate in Parkinson Disease

Abstract

IMPORTANCE Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).OBJECTIVE To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTSThe Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled.INTERVENTIONS Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURESThe prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid.RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability.CONCLUSIONS AND RELEVANCE Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00833690

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

“…Its blood concentration depends on dietary intake (e.g., meats, seafood, and beer have high purine content) [8], and excretion (which varies based on kidney function and genetically based differences in urate transporters) [9]. Peripherally generated urate may not readily cross the blood-brain barrier, as suggested by the 10-fold gradient from the blood to cerebrospinal fluid (CSF) [10]. It has been speculated that mutations in Uox during evolution, with resulting higher urate blood and central nervous system (CNS) levels in primates, conferred a selective advantage due to urate's antioxidant properties, amongst other theories [11].…”

Mendelian randomization: Progressing towards understanding causality

“…For example, to derive causality for urate levels for the development of PD would, in the strict sense, require the experimental modification of urate levels in healthy probands with a follow‐up long enough that a substantial number of these probands develop PD. More realistic RCTs are already being performed in which a urate precursor is being investigated as a disease‐modifying therapy in PD patients,4 but even if a therapeutic effect is shown, this does not answer the question about the causal effect of urate on the development of PD. Other criteria by Hill include the plausibility or the strength of the association and are easier to test, but they could be misleading given their subjectivity and vagueness.…”

Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis

“…Chronic elevation of urate is associated with an increased risk of developing gout and urolithiasis. In fact, symptomatic urolithiasis developed in 3 out of 50 (6%) participants receiving inosine for up to 24 months in a PD trial 33. In this small, short‐term trial, we did not observe any cases of urolithiasis.…”

“…Treatment was initiated gradually with one capsule taken twice a day for the first 2 weeks of the study. The inosine dose was then titrated at weeks 2, 4, 6, and 9 following a pre‐specified titration algorithm33 to achieve urate levels in the target range of 7–8 mg/dL. Inosine dosing was terminated after 12 weeks.…”

“…Indeed, urate elevation is rapidly advancing from the bench to the bedside in PD where a phase 2 clinical trial demonstrated safety and tolerability of inosine to increase serum and cerebrospinal fluid urate33, 34 and a phase 3 trial is ongoing to test the clinical efficacy of this approach (NCT02642393).…”