Inosine to Increase Serum and Cerebrospinal Fluid Urate in Parkinson Disease
Authors: Michael A. Schwarzschild, Alberto Ascherio, M. Flint Beal, Merit E. Cudkowicz, Gary C. Curhan, Joshua M. Hare, D. Craig Hooper, Karl D. Kieburtz, Eric A. Macklin, David Oakes, Alice Rudolph, Ira Shoulson, Marsha K. Tennis, Alberto J. Espay, Maureen Gartner, Albert Hung, Grace Bwala, Richard Lenehan, Elmyra Encarnacion, Melissa Ainslie, Richard Castillo, Daniel Togasaki, Gina Barles, Joseph H. Friedman, Lisa Niles, Julie H. Carter, Megan Murray, Christopher G. Goetz, Jeana Jaglin, Anwar Ahmed, David S. Russell, Candace Cotto, John L. Goudreau, Doozie Russell, Sotirios Andreas Parashos, Patricia Ede, Marie H. Saint-Hilaire, Cathi-Ann Thomas, Raymond James, Mark A. Stacy, Julia Johnson, Lisa Gauger, J. Antonelle de Marcaida, Sheila Thurlow, Stuart H. Isaacson, Lisbeth Carvajal, Jayaraman Rao, Maureen Cook, Charlise Hope-Porche, Lauren McClurg, Daniela L. Grasso, Robert Logan, Constance Orme, Tori Ross, Alicia F. D. Brocht, Radu Constantinescu, Saloni Sharma, Charles Venuto, Joseph Weber, Ken Eaton
Journal: JAMA Neurology (2014)

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 < .001for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006and <.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.