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.
BACKGROUND:The systematic conversion of adverse drug reactions (ADRs) into new therapeutic indications represents one of the oldest and most productive sources of repositioned drugs; however, it has not been subjected to formal mechanistic analysis. OBJECTIVES:This study aims to propose a mechanistic taxonomy of convertible ADRs and a structured workflow for translating documented adverse effects into testable repositioning hypotheses. METHODS:In this narrative review, historical cases of ADR-driven repositioning spanning five decades-from sildenafil and minoxidil to semaglutide-were analyzed and classified within a four-dimensional framework organized along the axes of: (1) target identity (on-target versus off-target conversion); (2) dose, route of administration, and reformulation; (3) patient population and clinical context; and (4) pharmacogenomic variability. RESULTS:Each historical case was successfully classified within the proposed taxonomy. A five-step theoretical workflow-comprising signal identification, taxonomic classification, mechanistic verification, feasibility assessment, and preliminary evidence search-was developed to operationalize the framework for prospective hypothesis generation. Computational tools including side-effect similarity networks, network pharmacology, and transcriptomic signature reversal were identified as means to support specific workflow steps. CONCLUSIONS:The proposed taxonomy and workflow provide a replicable, mechanism-informed approach to ADR-driven drug repositioning, while also delineating the pharmacological, regulatory, and methodological challenges that separate a repositioning signal from an approved therapeutic indication.
BACKGROUND:Midazolam (MDZ) is used for sedation in critically ill patients. Although previous studies have examined MDZ pharmacokinetics in ICU patients, the differential effects of acute kidney injury (AKI) and chronic kidney disease (CKD), particularly in cohorts including COVID-19 and non-COVID-19 patients, remain insufficiently characterised. OBJECTIVES:To investigate whether AKI and CKD are associated with dose-normalised exposure of MDZ, 1-hydroxy-midazolam (1-OH-MDZ) and 1-hydroxy-midazolam glucuronide (1-OH-MDZ-G) in critically ill adults. METHODS:In this retrospective observational study, ICU patients receiving continuous intravenous MDZ were included. Plasma concentrations of MDZ, 1-OH-MDZ and 1-OH-MDZ-G were converted to concentration-to-dose (C/D) ratios. Cross-sectional analysis used the first sample per patient; longitudinal analysis included all samples in GEE models. Analyses were adjusted for age, sex, BMI, COVID-19 status, CYP3A4 inhibitor use, APACHE IV score, time since MDZ initiation and CRP. RESULTS:Forty-seven patients contributed 137 samples. In the cross-sectional analysis, C/D ratios of MDZ and 1-OH-MDZ did not differ between patients with and without AKI, whereas 1-OH-MDZ-G C/D ratios were higher in AKI (median [IQR] 14.54 [6.14-26.20] vs. 4.53 [2.52-6.00]; p < 0.01). Longitudinal analysis showed that AKI (β = 0.87), AKI Stage 1 (β = 0.81), AKI Stages 2-3 (β = 0.97) and CKD (β = 0.72) were all significantly associated with higher 1-OH-MDZ-G C/D ratios (all p ≤ 0.03). No significant associations were observed for MDZ or 1-OH-MDZ. CONCLUSION:AKI and CKD are associated with accumulation of 1-OH-MDZ-G in critically ill patients. Monitoring 1-OH-MDZ-G may help identify patients at risk of prolonged sedation and adverse outcomes.
Cardiovascular complications of diabetes mellitus (DM) are responsible for morbidity and mortality in DM patients. Recent evidence highlights the pathophysiological role of the renin-angiotensin-aldosterone system in DM. This study determined whether chronic angiotensin (1-7) (Ang (1-7); 576 μg/kg, s.c., 4 weeks) treatment improves vascular reactivity in mesenteric small resistance arteries of streptozotocin-induced diabetic rats using a wire myograph system and to investigate the underlying mechanisms. Increased sensitivity to vasoconstrictors and decreased responses to endothelium-dependent vasodilators in diabetic rats compared to control rats were partially reversed by Ang (1-7) treatment. Nω-nitro-L-arginine methyl ester (L-NAME, 10-4 M) incubation significantly decreased vasorelaxant responses to acetylcholine (ACH, 10-10-10-5 M) in all groups except the diabetic group. Superoxide dismutase (SOD, 50 U/mL) incubation produced significant increases in vasorelaxant responses to ACH only in the diabetic groups. Glibenclamide (10-5 M), 4-aminopyridine (4-AP, 5 mM), indomethacin (INDO, 10-5 M), or catalase (CAT, 200 U/mL) incubations did not alter ACH responses in any experimental groups, whereas charybdotoxin (ChTX, 10-7 M) or apamin (APA, 10-7 M) produced significant decreases in ACH-induced vasorelaxation, similar in extent in the control and diabetic rats. Following co-incubation with L-NAME and INDO, ACH-induced vasorelaxation in 30 mM KCl pre-contracted arterial rings did not differ significantly between the groups. These findings indicate that improved nitric oxide bioavailability and reduced superoxide activity contribute to the beneficial vascular effects of Ang (1-7) in diabetic rat resistance arteries. Further in vivo studies are warranted to clarify its therapeutic relevance. SUMMARY: Ang (1-7) improves vascular function in diabetic rat resistance arteries. Treatment increases NO bioavailability and reduces oxidative stress. Vasoconstrictor sensitivity is decreased, improving endothelium-dependent vasorelaxation. Ang (1-7) restores vascular responses to endogenous vasoactive agents. Findings suggest Ang (1-7) as a potential target for diabetes-related vascular issues.
