LESSONS FROM FAILED CLINICAL TRIALS

Uric acid has become a leading candidate as a biomarker for tracing the progression of Parkinson’s disease, said Dr. Ira Shoulson, professor of neurology at the University of Rochester. Uric acid levels that are too high are responsible for gout, but higher uric acid levels at the middle ranges found in the Parkinson’s clinical trials turned out to reduce the risk for progression of Parkinson’s disease by approximately 25 percent, according to a published meta-analysis of observational studies, reported Shoulson (Weisskopf et al., 2007). The observational studies were spun off of three previous clinical trials of anti-Parkinson drugs. Not all the clinical trials turned out to be successful for their main purpose (i.e., finding a new treatment for Parkinson’s), but collection of blood and cerebrospinal fluid (CSF) uric acid during the trials turned out to be vital.

Identification of uric acid as a putative biomarker came about fortuitously. It occurred during a meeting of investigators to determine why a clinical trial of an anti-Parkinsonian drug, sponsored by two pharmaceutical companies, had failed. One of the investigators ventured that patients with higher uric acid at baseline seemed to fare the best. Once Shoulson and the other investigators analyzed the data more closely, they reached the same conclusion. In this particular trial, they found that male patients with the highest levels of uric acid especially had reduced their risk of Parkinson’s progression by about 50 percent, according to Shoulson, who described the data presented at a recent Society for Neuroscience meeting (Schwarzschild et al., 2006).

Furthermore, the results from the clinical trial suggested a possible mechanism for uric acid’s role. Uric acid is a strong antioxidant, and it is the product of the metabolism of purines. The link between higher levels of uric acid and reduction of Parkinson’s progression made mechanistic sense, they hypothesized, considering that oxidative mechanisms are implicated in the pathogenesis of Parkinson’s disease and other neurological disorders (Floyd, 1999). But what specific target was protected from oxidation by uric acid?

The failed clinical trial provided a clue because it also had collected data on levels of the dopamine transporter in the striatum by using SPECT images of [123I] β-CIT uptake (the striatum’s loss of dopamine transmission is one of the central lesions in Parkinson’s disease). On subsequent analysis, investigators found that uric acid had a dose-dependent effect on the levels of dopamine transporter: patients with the lowest levels of uric acid had the highest loss of dopamine transporter over time,



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement