Concerns regarding local and systemic adverse effects associated with long-term use of corticosteroids has motivated the study of new therapeutic approaches for psoriasis treatment. This study evaluated the efficacy of a novel nanoformulation loaded with a hydrogen sulfide (H₂S)-releasing dexamethasone derivative (Dexa-TBZ) in an experimental psoriasis model. Psoriasis was induced with topical imiquimod, and mice were treated for 4 days with dexamethasone- (Dexa, control) or Dexa-TBZ-loaded nanoformulations. Erythema and scaling (assessed by a modified Psoriasis Area Severity Index), myeloperoxidase (MPO) activity, and spleen size were assessed for efficacy. Daily topical treatment with either Dexa or Dexa-TBZ reduced scaling and erythema, with the last most likely related to decreased inflammation, as suggested by a marked reduction in MPO activity and neutrophil infiltration. Both treatments also reduced epidermal thickening, indicating comparable local therapeutic effects. However, Dexa caused a greater reduction in circulating leukocytes and spleen size, suggesting higher systemic exposure despite topical administration. In contrast, Dexa-TBZ showed limited systemic effects. Although Dexa-TBZ did not demonstrate superior local efficacy, its lower systemic impact suggests an improved safety and tolerability profile, which may be advantageous for the long-term topical treatment of chronic conditions such as psoriasis.
Poor biorelevant stability can complicate oral drug development, but its relevance depends on systemic exposure to degradation products and their associated safety risks. pH-dependent degradants represent physiology-driven transformation products that do not align with conventional definitions of impurities or metabolites, complicating their evaluation during development. This work presents an integrated, exposure-based risk assessment framework to evaluate their clinical relevance. Compound A degradation was evaluated under biorelevant conditions, gastric pH (pentagastrin)-modified rat and dog pharmacokinetic studies, mechanistic absorption modeling, pharmacological evaluation, and mutagenicity assessment. Compound A exhibited rapid acid-mediated degradation in fasted-state simulated gastric fluid ( 50
To develop an exploratory flow-through time-lapse macro-imaging framework combining rule-based image analysis and multimodal large language models (LLMs) for comparing release phenotypes of nifedipine osmotic pump tablets. Sixteen marketed products, comprising Adalat OROS and 15 generics, were imaged in triplicate for 36 h under sequential pH 1.0 (2 h) and pH 6.8 (34 h) conditions at 37 ± 0.5°C. Images acquired every 30 s were analyzed using a pixel color-based drug similarity method (PCDS), the Dis-GPT agent, and a pharmaceutical knowledge-base-assisted DIS Chatflow. The framework captured drug-layer extrusion, local aggregation, release continuity, and push-layer morphology. Eight generics (02, 03, 04, 10, 12, 13, 15, and 16) were classified as similar to the reference by all three methods. Product 08 was consistently classified as different, exhibiting granular extrusion, bead-like aggregation, and reduced continuity; products 06 and 07 showed method-dependent deviations in release timing and push-layer extrusion. Flow-through time-lapse imaging revealed process-level release features not represented by cumulative dissolution profiles. Combining transparent pixel-based measurements with structured LLM analysis provides an exploratory framework for comparing visible release phenotypes and generating hypotheses about release mechanisms in controlled-release tablets.
Nanvuranlat (JPH203, NVL) is a selective L-type amino acid transporter 1 (LAT1) inhibitor that shows antitumor activity despite rapidly declining blood concentrations. This study investigated whether its long-lasting inhibition of LAT1 is associated with its cellular retention in HuCCT-1 cells, a human cholangiocarcinoma cell line. After NVL exposure and washout, LAT1 activity was evaluated by [14C]leucine uptake, and cell-associated NVL was quantified. The role of cancer-type OATP1B3 (Ct-OATP1B3) was examined using siRNA-mediated knockdown. Tumor retention was assessed in mice bearing HuCCT-1 xenografts. Following preincubation with 100 µM NVL and a 4-h washout, [14C]leucine uptake was 60.4
Bradykinin-potentiating peptides (BPPs), found in snake venom, are known to modulate cardiovascular functions, but their susceptibility to enzymatic degradation remains poorly understood. Models were generated using AlphaFold-Colab for five small BPPs (< 9 amino acids) that did not have experimentally solved structures, and those BPPs which had reliable predictions of structure (pLDDT > 80) were used for docking studies. Protein-peptide docking experiments were done using HADDOCK for studying the interaction between wild-type (WT) and mutant serratiopeptidase with BPPs. After selecting the best complex, simulation of the complex was done using molecular dynamics (MD) simulations for 100 ns and binding energy determination using MM/PBSA analysis. For checking the mechanical stability of the protein-peptide complexes, Steered MD was performed. HADDOCK docking identified BPP-4 as a favorable binder of WT and mutant serratiopeptidase supported by a HADDOCK score of -109.1 ± 5.2 and minimal restraint violations. MD simulations revealed greater stability in the mutant complex supported by persistent hydrogen bonds, reduced RMSD/RMSF fluctuations, restricted conformational sampling in PCA, favorable MM/PBSA energy contributions, and a more stable conformational ensemble in cluster analysis. The Steered MD simulation showed a higher rupture force in the mutant BPP-4-serratiopeptidase complex compared to the WT. Computational analysis identified BPP-4 as a promising serratiopeptidase-binding peptide, with differences in binding affinity and mechanical stability between WT and mutant complexes. The results offer insight into BPP-serratiopeptidase recognition at the molecular level and set the basis for future experiments on peptide binding.
