Inhibition of xanthine dehydrogenase/oxidase (allopurinol), a common treatment for gout may help reduce the risk for neurodegenerative diseases, according study findings published in the journal PLoS One.
Researchers conducted a population-based, case-control study in 2009 with Medicare beneficiaries with Part D coverage. Patients with Parkinson disease (PD), Alzheimer disease (AD), and amyotrophic lateral sclerosis (ALS) were identified and compared with beneficiaries without these conditions. Prescription claims were restricted to 2006-2007 to ensure that these medications were prescribed >1-year before neurodegenerative disease diagnosis.
The conditions PD, AD, and ALS were identified using the International Classification of Diseases Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Patients were classified into 4 groups: PD only (N=28,679), AD only (N=8,332), ALS only (N=1,341), or mixed PD/AD/ALS (N = 4,533). Participants were not matched to control individuals (N=334,387).
The researchers utilized Medicare Part D claims data to identify all medications used by all patients from 2006-2007. Individuals were included as a medication user if there was ≥1 prescription claim for the respective medication. Active ingredients and their respective biological targets were identified for all medications observed; of the 768 active ingredients identified, 723 biological target-action pairs were found, and 141 target-action pairs had >10 beneficiaries. Multinomial logistic regression models were used to calculate odd ratios [ORs]; covariates were accounted for. All inverse associations identified were replicated in a cohort study containing an active comparator group; hazard ratios [HRs] were estimated using Cox proportional hazard regression, and the same covariates were accounted for.
Of the 141 target-action pairs, 30 were associated with decreased risk for at least 1 neurodegenerative disease. Four of the 30 had a calculated OR ≤0.80, equivalent to a ≥20% reduction in risk for all four groups.
The most consistent association between medication and reduced neurodegenerative disease risk included:
- xanthine dehydrogenase/oxidase blockers,
- bifunctional purine biosynthesis protein PURH blockers, and
- vascular endothelial growth factor A targets.
The target-action pairs are represented by allopurinol (mean OR, 0.77), methotrexate (mean OR, 0.79), and carvedilol (mean OR, 0.80, respectively).
Specifically, allopurinol was associated with a 23% mean risk reduction for neurodegenerative disease compared with control individuals.
Allopurinol, carvedilol, and methotrexate were used in the following replication cohort study against active comparators. Inverse associations were confirmed for allopurinol and carvedilol, and risk reduction was similar to the original case-control study. For allopurinol, the HR was 0.77 (95% CI, 0.62-0.95) and 0.81 (95% CI, 0.67-0.99) for carvedilol. An inverse association was not able to be confirmed for methotrexate.
Limitations of this study include that Medicare beneficiaries are older than age 65, which could prevent generalizability to younger individuals; additionally, using ICD-9-CM codes for condition identification may exclude patients who were misdiagnosed or those who lack a formal diagnosis.
Song Y, Racette BA, Camacho-Soto A, et al. Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries. PLoS One. Published online May 17, 2023. doi:10.1371/journal. pone.0285011.