TNCE-3

Oral dopaminergic treatment is the cornerstone of Parkinson's disease (PD) management. However, progressive shortening of oral levodopa's effect, along with the limited efficacy of enzyme inhibitors and dopamine agonists, does not allow to adequately control motor and non-motor complications characterizing advanced PD. At this stage, device-aided therapies (DATs), including infusion treatments, are warranted to guarantee an adequate quality of life.

We review current and upcoming infusion therapies for PD, with a particular focus on their efficacy and safety data. Moreover, we provide an overview of current knowledge and open issues on patient selection and specific DAT choice.

Recent EAN/MDS-ES guidelines suggest infusion therapies for advanced PD, yet several challenges remain, including limited access, delayed referrals, and patients' hesitancy. The '5-2-1' criteria and tools like MANAGE-PD aid early identification of eligible candidates, but treatment decisions often do not account for patients' preferences. Current trends favor early DATs implementation, as soon as motor fluctuations appear and before the disability onset. Emerging infusion therapies (e.g. foslevodopa-foscarbidopa) will boost this tendency. Enhancing DATs accessibility and inclusivity in clinical trials are key priorities. Finally, regenerative therapies including putaminal infusion of neurotrophic factors and dopaminergic neuron precursors may transform advanced PD care.

Inflammation and metabolic disorders like diabetes mellitus share complex pathways that drive disease progression, emphasizing the urgent need for multi-target therapeutics for effective management. In the present study, a series of 1,3,4-thiadiazole derivatives (14-26) bearing phenyl and benzyl substitutions at fifth position of thiadiazole core were synthesized and characterized with spectroscopic techniques like FT-IR,¹H NMR,¹³C NMR and EI-MS. The biological evaluation revealed promising inhibition of the key inflammatory enzymes (COX-2 and 5-LOX), and metabolic enzymes (α-glucosidase and α-amylase) linked to type 2 diabetes. Among the tested derivatives, compound 16 exhibited the most potent dual action, with IC₅₀ values of 8.78 μg/ml (COX-2), 4.51 μg/ml (5-LOX), 69.41 μg/ml (α-glucosidase), and 50.50 μg/ml (α-amylase), demonstrated moderated activity as compared to the standard inhibitors. Compound 26 also exhibited significant anti-inflammatory, with IC50 values of 2.03 μg/ml (COX-2), 6.03 μg/ml (5-LOX). Molecular docking studies further supported the biological findings, revealing binding interactions of these derivatives with the active sights of targeted enzymes, reinforcing their potential as lead candidates for dual acting anti-inflammatory and anti-diabetic agents. These findings suggest that 1,3,4-thiadiazole derivatives have the potential to develop as multi-functional therapeutics to target inflammation and metabolic dysregulations.