Tolcapone

Catechol-O-methyltransferase (COMT) inhibitors-Tolcapone, Entacapone, and Opicapone-are adjunct therapies for advanced Parkinson's disease (PD), improving motor control. Their distinct safety profiles may influence clinical decisions and patient adherence. This study provides a comprehensive descriptive analysis of adverse events (AEs) reported for these drugs and a comparative safety assessment based on post-marketing AE reports and drug sales data from 2018 to 2023. A retrospective analysis was conducted using data from the FDA Adverse Event Reporting System (FAERS). AEs were categorized by severity and compared across COMT-inhibitors. Drug utilization trends were evaluated through retail and hospital sales data, expressed as standard units and market share. AE incidence was normalized for drug exposure using the median number of pills per day. Statistical comparisons were performed using Fisher's exact test to assess differences in AE rates. Entacapone was sold 100 times more than Opicapone and 1000 times more than Tolcapone. When normalized for drug exposure, total AEs were significantly lower for Entacapone than Opicapone (OR = 0.0435, p < 0.001) and Tolcapone (OR = 0.1397, p < 0.001). Tolcapone also exhibited a significantly lower AE risk than Opicapone (OR = 0.3119, p < 0.001). Similarly, Entacapone had significantly fewer serious AEs than Opicapone (OR = 0.0732, p < 0.001) and Tolcapone (OR = 0.0872, p < 0.001), indicating a more favorable safety profile. This is the first study directly comparing the safety profiles of COMT-inhibitors head-to-head. Entacapone appears to be the safest long-term COMT-inhibitor, with the lowest risk of both serious and non-serious AEs. A long-term, prospective clinical trial is warranted to overcome retrospective limitations and confirm these findings.

Tolcapone, a clinically approved drug for the treatment of Parkinson’s disease as an adjunct therapy, has recently emerged as a potential modulator of amyloid‐β aggregation and toxicity, which are hallmark features of Alzheimer’s disease and are also involved in ocular neurodegenerative disorders, including glaucoma and age‐related macular degeneration. Despite these noteworthy findings, the molecular basis of the interaction between amyloid‐β and tolcapone remains poorly understood, and the mechanisms by which tolcapone affects metal–amyloid‐β species have yet to be explored. In this work, we investigate the binding interactions of tolcapone with both copper‐free amyloid‐β and copper‐associated amyloid‐β complexes, using a combination of techniques including UV–vis spectroscopy, circular dichroism, mass spectrometry, and surface plasmon resonance. The results reveal that tolcapone binds directly to amyloid‐β monomers. Furthermore, in vitro assays confirm the capacity of tolcapone to act as a radical scavenger and to compete with amyloid‐β for the binding of copper ions. Altogether, our findings suggest that tolcapone exerts a multifaceted protective effect, potentially inhibiting toxic metal‐free and metal aggregation pathways by preventing metal coordination to amyloid‐β or disrupting preformed amyloid‐β–metal complexes, thus offering new perspectives to explore and develop its analogs for the treatment of neurodegenerative disorders.