Background/Objectives: Although α-blockers are commonly used to treat lower urinary tract symptoms in men with benign prostatic hyperplasia (BPH), their differential neuropsychiatric safety profiles remain underexplored. Some studies have suggested an increased risk of cognitive decline, mood disorders, and falls, but the results remain inconclusive. Methods: We conducted a large retrospective cohort study using the TriNetX global network, identifying over 264,000 men treated with a single α-blocker between 2005 and 2023. Patients were grouped by α-blocker type-tamsulosin, doxazosin, terazosin, alfuzosin, silodosin, or prazosin-and matched 1:1 using propensity scores to adjust for demographic, clinical, and psychosocial variables. The primary outcomes were new-onset dementia, depression, and unintentional injuries, assessed at 1-, 3-, and 10-year intervals. The median follow-up duration was approximately 5.5 years, ranging from 1824 to 2200 days across cohorts, indicating balanced observation periods among the six α-blocker groups. Results: Among the included patients, tamsulosin (n = 213,690) and prazosin (n = 1184) were associated with significantly higher risks of neurodegenerative, psychiatric, and injury-related outcomes. Alfuzosin (n = 10,138) exhibited the most favorable safety profile across all endpoints. The findings remained robust in sensitivity analyses, excluding patients with prior malignancy or other α-blocker exposure. Conclusions: Substantial differences in long-term neuropsychiatric safety exist among α-blockers. Given its favorable profile, alfuzosin may be the preferred agent in patients at elevated risk of cognitive or psychiatric disorders. These findings highlight the need for individualized α-blocker selection and long-term pharmacovigilance in BPH management.

Neuroinflammation is a key driver of Alzheimer's disease and an emerging therapeutic target. The p38/MK2 pathway regulates microglial cytokine production, yet previous attempts have not yielded modulators with clinically suitable properties. Here, we apply an integrative structure-guided and screening strategy to identify small-molecule disruptors of the p38/MK2 protein-protein interaction (PPI). Virtual screening of FDA-approved drugs prioritized nilotinib, a BCR-ABL inhibitor, as a putative PPI disruptor. Biochemical and molecular dynamics analyses confirmed that nilotinib binds to p38, blocks MK2 association, and suppresses cytokine release in microglia. Guided by these findings, we developed a lysate-based TR-FRET ultrahigh-throughput assay that identified additional inhibitors, including α1-adrenergic antagonists doxazosin, terazosin, and alfuzosin. These compounds suppressed cytokine induction via docking groove blockade. Together, these results establish a non-ATP-competitive approach for selectively targeting the p38/MK2 complex and highlight the translational potential of drug repurposing to modulate neuroinflammation in Alzheimer's disease.

Existing methods for AFZ estimation lacked sensitivity for picoscale detection in biological samples, faced matrix interferences, and used environmentally harmful solvents. A sensitive, selective, and eco-friendly microwave-assisted fluorodensitometric probe was developed for picoscale estimation of AFZ in pharmaceutical formulations and human plasma. The method utilized a microwave-assisted microlevel Hantzsch reaction for the generation of a fluorodensitometric probe for AFZ derivatization in the microenvironment of a silica plate. A design of experiments (DoE) approach was implemented using a Plackett-Burman design for risk assessment and a minimum run resolution IV design for response surface analysis. HPTLC-MS was used for the characterization of the fluorodensitometric probe generated by microwave-aided microlevel condensation of organic liquids and AFZ. The method demonstrated linearity in the range of 10-50 pg/band with high sensitivity (LOD: 3.0 pg/band, LOQ: 10.0 pg/band). Precision and accuracy were within acceptable limits. The method was successfully applied to pharmaceutical formulations and different plasma samples. The proposed method offers a sensitive, selective, and environmentally friendly approach for AFZ estimation at picoscale levels, adhering to white analytical chemistry principles and the QbD approach.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Because of its high potential for spreading and its limited response to treatment, UM remains a clinical challenge. Previous studies suggest that clinical adrenergic receptor (AR) antagonists might be effective in the treatment of UM. This study reports the antitumor activity of α-blocker in UM spheroids generated from α1A- and α2A-AR-positive UM cell lines. These cell lines were derived from primary tumors or hepatic metastases and differed in their genetic risk status for metastasis. Drug screening with UM spheroids revealed that prazosin and doxazosin dose-dependently reduced viability, whereas terazosin, alfuzosin, silodosin, tamsulosin, and phenoxybenzamine were found to be inefficient. Prazosin induced apoptosis, resulting in the disintegration of UM spheroid morphology and growth inhibition. Additionally, prazosin prevented UM spheroid cell outgrowth and long-term survival, indicating potential for tumor control. Like the selective α1A-AR antagonist RS17053, prazosin inhibited the formation and growth of UM spheroids stimulated by the α1-agonist phenylephrine. This suggests a tumor-preventive effect through the blockade of α1A-AR. The present study highlights the responses of UM spheroids to α-AR antagonists and demonstrates that prazosin, doxazosin, or RS17053 may be a treatment option for preventing UM tumor recurrence or metastasis.