ABSTRACT Background Observational studies report that prolonged infusions of piperacillin‐tazobactam may enable the achievement of an optimal clinically targeted free drug concentration above the minimum inhibitory concentration (fT > MIC). Objectives This study aimed to assess the feasibility of a randomized controlled trial (RCT) comparing standard to prolonged infusions of piperacillin‐tazobactam in the obese population. Methods In this open‐label RCT, patients with a body mass index (BMI) of 30 kg/m 2 or higher who initiated piperacillin‐tazobactam were recruited and randomly assigned to receive either standard or prolonged infusions of the antibiotic. Feasibility and safety outcomes were assessed. A blood sample was collected 24 h after the intervention to measure total piperacillin concentrations, with an exploratory aim of determining the proportion of patients who achieved 100% fT > MIC. Results A total of 45 patients were recruited at a rate of 7.2 patients per month with a consent rate of 42.1%, achieving these feasibility objectives. Adherence to blood sampling was 77.8%, below the 80% objective. On an exploratory basis, the proportion of patients who achieved 100% fT > MIC 24 h postintervention was 64.3% in the prolonged‐infusion group and 55.6% in the standard‐infusion group ( p = 0.725). There was no significant difference in the safety outcomes ( p = 0.756). Conclusion This first RCT evaluating prolonged infusions of piperacillin‐tazobactam in the obese population demonstrated the feasibility of the protocol. Although not statistically significant, the results suggest a favorable trend for fT > MIC attainment and no safety signal for prolonged infusions and support the conduct of a larger scale RCT. Trial Registration Clinical trial registration: NCT #06690905
ABSTRACT Background Angiotensin receptor blockers (ARBs) have demonstrated neuroprotective effects in preclinical models of Parkinson's disease (PD), but individual ARBs differ in pharmacological properties that may influence their neuroprotective potential. Objectives Using large‐scale hospital electronic health records of the University of California health system, we tested whether specific ARBs are associated with lower PD risk. Methods We conducted a new‐user, active‐comparator cohort study in the University of California Health Data Warehouse, encompassing 890 712 hypertensive patients across six academic medical centers from 2012 to 2025. Cox proportional hazards models estimated hazard ratios for individual ARB associations with incident PD, adjusting for demographics, nine preindex comorbidities, and index date. Robustness was assessed through propensity score matching and negative‐control analysis. Results Drug‐specific Cox analysis identified irbesartan (HR = 0.588, 95% CI 0.434 to 0.796, p = 0.0006) and olmesartan (HR = 0.797, 95% CI 0.665 to 0.956, p = 0.015) as associated with lower PD risk. Irbesartan survived Bonferroni correction for multiple comparisons, and propensity score matching supported both associations. Conclusion In this large multicenter EHR cohort, irbesartan and olmesartan were associated with lower incident Parkinson's disease risk. These findings support further investigation of the renin‐angiotensin system as a therapeutic target in Parkinson's disease and may inform the development or repurposing of agents with favorable central nervous system penetration and neuroprotective potential.
ABSTRACT Objectives To investigate the influence of sex, age, body weight, smoking habits, and co‐medications on sertraline pharmacokinetics in a routine clinical setting. Methods This retrospective observational study analyzed 177 predominantly inpatient therapeutic drug monitoring records from 101 patients receiving sertraline as monotherapy or polytherapy. Pharmacokinetic parameters—serum concentrations (CSER), concentration‐to‐dose ratio (CDR), weight‐normalized CDR (CDR/kg), apparent clearance (CL/F), and metabolite‐to‐parent ratio (N‐SER/SER)—were compared across subgroups defined by sex, age (< 18; 18–65; > 65 years), BMI, smoking, and co‐medications. To address the nonindependence of repeated measurements, analyses were complemented using linear mixed‐effects models and a sensitivity analysis restricted to one observation per patient. Results Descriptive analyses suggested higher CDR/kg in males and higher CSER in elderly patients. After accounting for within‐patient clustering, the increase in CDR/kg across BMI categories remained the most consistent finding, likely reflecting mathematical normalization. The higher CSER observed in elderly patients persisted in the mixed‐effects model but not in the sensitivity analysis, although the direction of effect remained consistent. Sex‐related differences were not robust after adjustment and were largely attributable to body weight. Smoking showed no measurable effect. Among co‐medications, carbamazepine showed the most consistent pharmacokinetic signal, whereas other findings were less consistent. Conclusion Elderly age may contribute to higher sertraline concentrations; however, its effect appears modest after accounting for clustering. Sex differences are largely explained by body weight, and smoking does not appear to influence pharmacokinetics. Carbamazepine showed a consistent induction pattern, whereas other co‐medication findings should be considered exploratory.
BACKGROUND:SB216763 has demonstrated efficacy in treating pulmonary fibrosis in animal models, but its underlying mechanisms remain poorly understood. This study used network pharmacology, molecular docking, and molecular dynamics simulations to explore the molecular mechanisms by which SB216763 exerts therapeutic effects on pulmonary fibrosis. METHODS:The targets of SB216763 were screened using the PharmMapper database, while pulmonary fibrosis-related targets were obtained from GeneCards and OMIM databases. A Venn diagram generated from these datasets highlighted overlapping targets. Protein-protein interaction networks were constructed using the STRING database and Cytoscape software to assess target importance. GO and KEGG enrichment analyses using the Metascape database revealed relevant biological functions and signaling pathways of SB216763 in the treatment of pulmonary fibrosis. Molecular docking investigated the binding affinity and binding mode of SB216763 with GSK-3β. Molecular dynamics simulations further confirmed the stability of the complex formed by SB216763 and GSK-3β. Finally, Western blotting, Griess assays, and ELISA were employed to validate the effect of SB216763 on macrophage functional plasticity in pulmonary fibrosis. RESULTS:Network pharmacology analysis identified the following three key targets of SB216763 in pulmonary fibrosis: AKT1, GSK3B, and TGFBR1, along with the PI3K-AKT signaling pathway. Molecular docking and dynamics simulations revealed that SB216763 primarily interacts with GSK-3β through hydrogen bonds and hydrophobic interactions. In vitro validation demonstrated significant anti-inflammatory and antifibrotic effects of SB216763. Additionally, SB216763 exhibited good safety in macrophages. CONCLUSIONS:This study provided new insights into the mechanisms of SB216763 in the treatment of pulmonary fibrosis.
The recent decision to establish a single pivotal trial as the default evidentiary standard for Food and Drug Administration (FDA) approval marks a substantive shift in the architecture of regulatory proof. This marks a shift from replication-based validation to a coherence-based model of sufficiency, beyond a procedural adjustment. Because FDA standards likely influence global development strategies, this change will likely extend beyond the United States. Although accelerating access and reducing development costs are legitimate objectives, the reform raises methodological and epistemological concerns. The statistical rationale does not fully incorporate the contextual factors that influence false-positive risk, including prior plausibility and statistical power. Prior plausibility remains informal, and post-marketing evidence seldom restores the epistemic security provided by independent replication. Replication is not merely a statistical redundancy but rather a structural safeguard of robustness and external validity. Without explicit safeguards, increased regulatory flexibility may generate heterogeneity in evidentiary thresholds and progressively weaken the discriminative function of health technology assessment.
