Traumatic brain injury (TBI) induces secondary neuroinflammation driven by oxidative stress, inflammasome activation, and immune remodeling, yet specific mechanism-guided pharmacological interventions remain limited. This study established an artificial intelligence (AI)-integrated network pharmacology and multi-omics framework to evaluate whether hydroxytyrosol (HT), an olive-derived natural polyphenol, may regulate TBI-related neuroinflammatory targets centered on the TXNIP/NLRP3 inflammasome axis. Starting from the SMILES structure of HT, potential targets were predicted using PharmMapper, SwissTargetPrediction, and the Similarity Ensemble Approach and were standardized to UniProt identifiers. TBI-associated genes were integrated from GeneCards, DisGeNET, OMIM, and the Therapeutic Target Database. The overlapping target set was analyzed using STRING-based protein-protein interaction (PPI) networks, MCODE, CytoHubba, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Public GEO transcriptomic datasets (GSE123831 and GSE104687) were used for cross-platform expression validation, differential expression analysis, and exploratory CIBERSORT-based immune infiltration estimation. Random forest (RF), multilayer perceptron (MLP), graph convolutional network (GCN), graph attention network (GAT), SHAP/LIME explainability analysis, LASSO inflammatory-risk scoring, and two-sample Mendelian randomization (MR) were further applied for target prioritization, immune phenotype mapping, and genetic association analysis. Seventy-three overlapping HT-TBI targets were identified. PPI and topology analyses prioritized TXNIP, NLRP3, CASP1, MAPK1, and TP53 as key hubs enriched in inflammasome activation, oxidative stress, apoptosis, and NOD-like receptor signaling. TXNIP, NLRP3, and CASP1 were consistently upregulated in both TBI transcriptomic datasets.LM22-based immune deconvolution suggested increased pro-inflammatory immune signatures and a positive TXNIP-M1 macrophage association (r = 0.63, p < 0.001), which should be interpreted as a transcriptome-derived hypothesis rather than validated murine immune-cell proportions. AI-based models consistently ranked TXNIP/NLRP3 as high-contribution features under internal validation, and removal of these targets reduced model performance. A five-gene inflammatory score achieved an internally evaluated AUC of 0.87, while two-sample MR supported positive genetic associations involving TXNIP expression, TBI risk, NLRP3 and IL-1β expression. Collectively, these findings prioritize the TXNIP/NLRP3/CASP1 module as a computationally supported candidate mechanism through which HT may influence oxidative stress-inflammasome-immune coupling in TBI. This study provides an interpretable drug-target-pathway-phenotype framework and identifies TXNIP, NLRP3, and CASP1 as priority nodes for future experimental validation.
Propofol pharmacokinetics in neonates is characterised by pronounced developmental variability, and performance of existing models in preterm neonates remains insufficiently characterized. We systematically evaluated published propofol population pharmacokinetic models suitable for neonates and developed a new literature-supported meta-model. A new dataset was obtained using opportunistic volumetric absorptive microsampling from preterm and term neonates. Neonates (n=40, median gestational age: 32.7 weeks) receiving 2 mg/kg propofol for procedural sedation were studied. Blood samples (10 µl) were collected to Mitra™ microsampling devices during 24 hours after propofol dose coinciding with routine clinical blood sampling. Propofol concentrations were quantitated with HPLC-MS/MS method. Three published propofol population pharmacokinetic models were compared using numerical and graphical tests of goodness-of-fit and predictive performance. Population modelling was conducted using NONMEM® and the $PRIOR subroutine to describe the time-course of whole-blood concentrations of propofol. No published model adequately described propofol concentration-time course in our new dataset. A sensitivity analysis of clearance maturation structures showed that replacing the base model with alternative formulations of postnatal adaptation (discrete step), postmenstrual age-based sigmoidal maturation, or higher allometric exponents for clearance (1.11 and 1.20 instead of 0.75) decreased the predictive performance of the model. A population pharmacokinetic meta-model incorporating prior information from published neonatal models was developed. Clearance maturation was parameterised as the product of a gestational component and an early postnatal adaptation component. All clearance and distribution parameters were scaled with allometric weight scaling. The final model estimated propofol concentration-time course with reasonable precision and predictive performance in preterm infants.
The d-enantiomeric peptide RD2 (named Contraloid or PRI-002 in clinical trials) was developed for the direct disassembly of toxic amyloid-β (Aβ) oligomers, which are the most neurotoxic aggregate species and play a key role in the development and progression of Alzheimer´s disease (AD). PRI-002/RD2 already demonstrated its safety and tolerability in three phase I clinical trials in young healthy volunteers and patients with mild neurocognitive impairment (MCI) or mild dementia due to AD. Results from a phase II clinical trial with PRI-002/RD2 are expected this year, which was designed to demonstrate safety and efficacy of PRI-002/RD2 in patients at an early stage of AD.The objective of this study was to evaluate the effect of age, sex, genotype and food on the pharmacokinetics of intravenous or orally administered RD2 in male and female transgenic APPswe/PS1ΔE9 (APP PS1) (n=62) or wild type (wt) mice (n=169) under fed and fasted conditions. Age and concomitant food intake influenced the pharmacokinetics of RD2. Slightly higher plasma and brain levels were observed in young compared to old wt mice. However, the effect of food on plasma levels depended on the RD2 dose administered. While at lower doses (200 mg/kg) the effect was substantial, plasma levels were 15 times higher in fasted than in non-fasted animals, the effect was only minor at higher RD2 doses (600 mg/kg).The results of this study indicate the important influence of prior food intake on the bioavailability of the compound, which may also apply to patients and is therefore of interest in further clinical development.
RNA therapies are transforming the treatment landscape for several rare, severe, and previously untreatable diseases. Regulatory approval only permits the medicine to be marketed; it does not determine whether a public health system will fund it. In Europe, this typically relies on national reimbursement bodies, following a Health Technology Assessment (HTA) or comparable processes.Despite the clinical promise of RNA therapeutics, they pose a significant challenge for funding decision makers due to their high costs, limited evidence on long-term effectiveness, and often narrow indications. Therefore, this targeted comparative review was conducted to analyse national HTA decisions and reimbursement policies for selected non-viral RNA therapeutics across six countries: Ireland, England, France, Germany, Canada, and the United States.HTA agencies across the reviewed countries generally issued favourable recommendations for RNA therapeutics reimbursement despite different assessment criteria, citing clinical effectiveness, unmet need, and budget impact as central factors. However, HTA agencies also expressed concerns about long-term benefit, meeting cost-effectiveness thresholds, and limited real-world evidence of these therapeutics. RNA therapeutics were often reimbursed under conditional reimbursement schemes or managed entry pathways. Countries with formal orphan drug pathways or flexible reimbursement mechanisms (e.g. Germany, England) were more likely to facilitate earlier access.With the accelerating growth in new RNA therapeutics, there needs to be consideration of the capacity for, and appropriateness of, current approaches of assessment and reimbursement, as well as the extent to which harmonisation of methods can support equitable and evidence-based access to patients across Europe.
Intratympanic (IT) corticosteroid therapy is a well-established intervention for sudden sensorineural hearing loss (SSNHL), yet its optimal dosing remains undefined. This study aimed to conduct an integrated preclinical and clinical evaluation of high-concentration IT dexamethasone phosphate (Dex-P), focusing on pharmacokinetics (PK), safety, and preliminary efficacy. The study comprised three parts. Part A and Part B evaluated the perilymph and plasma PK of cynomolgus monkeys. Part C assessed the plasma PK, safety, and hearing recovery of standard treatment-failure SSNHL patients following three IT injections of Dex-P (20 or 40 mg/mL, q3d). Preclinical PK data demonstrated the superiority of IT treatment, achieving high and sustained drug levels in the perilymph that were not detected via systemic administration. High-concentration IT injection led to disproportionate increase in perilymph exposure relative to the dose increment, while the corresponding plasma exposure was approximately following the dose proportionality. In SSNHL patients, high-concentration IT administration was well-tolerated with no dose-limiting toxicity. Systemic exposure increased approximately in proportion to the dose increment, and no significant accumulation was observed. Hearing improvement was modest. Although not statistically significant, a greater pure-tone average improvement was observed in the 40 mg/mL group (5.69 dB) compared to the 20 mg/mL group (3.06 dB). High-concentration IT Dex-P (up to 40 mg/mL) is a feasible and safe option for the salvage treatment of SSNHL. The trend toward better hearing outcomes, combined with its enhanced local target-site exposure and favourable safety profile, provides a rationale for further investigation in larger, controlled clinical trials to optimize therapeutic efficacy.
With a metered volume of 15 µL per actuation, the Respimat® Soft Mist Inhaler is well-suited for use in inhalation therapies with potent and soluble drugs. To expand its therapeutic range, an alternative nozzle concept was explored that replaces the twin impinging jets with a single jet impacting a baffle perpendicularly. Maximizing the impaction angle enables a more efficient droplet generation. This may allow for a higher liquid volume delivered per actuation at lower pressure. As a result, less potent or less soluble drugs— potentially including biologics—might be administered. Additionally, the enlarged nozzle orifice is expected to be less prone to clogging than narrow twin microchannels. This reduced clogging risk may allow the use of suspension formulations. An initial design of experiments identified key parameters influencing aerosol performance, mainly droplet size and residue of not atomized liquid. While inhalable droplets (∼5 µm) were generated, high residual values indicated inefficient atomization. Computational fluid dynamics simulations revealed that oversized baffle diameters compromise atomization efficiency by decelerating the radially spreading liquid film on the baffle surface, leading to droplet accumulation. In silico droplet formation was observed via: (i) early detachment from the advancing liquid front, and (ii) through disintegration of the liquid sheet at the baffle edge. A follow‑up DoE using smaller baffle diameters substantially reduced residue while maintaining inhalable droplet sizes. This alternative nozzle concept therefore presents a promising approach to broaden the therapeutic scope of the Respimat Soft Mist Inhaler by increasing the delivered volume per actuation.
Osteochondral defects have become a common clinical problem. The cartilage-bone interface is complex, and regenerative biomaterials are limited. This is the first study to integrate Continuous plastic flow synthesis (CPFS) derived Zn-doped hydroxyapatite into an electrospun PVA nanofibrous membrane for osteochondral repair. Combined structural and spectroscopic analysis revealed a preserved apatite lattice after zinc integration, with a strong inorganic-polymeric interfacial interaction. The fabricated membrane exhibited smooth nanofibers with an average diameter of 272 ± 2.21 nm, in which Zn-HA was uniformly dispersed. The nanofibrous membrane exhibited considerably better antibacterial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa than Zn-HA. In vitro results confirmed good viability of osteoblasts. In vivo assessment in an osteochondral defect model revealed nearly complete defect repair after 8 weeks, with well-organized trabecular bone formation and restoration of the bone-cartilage structure without a significant inflammatory response. Collectively, these findings reveal synergistic osteoregenerative and antibacterial activity, suggesting that the nanofibrous membrane may serve as a potential material for osteochondral tissue engineering.
Ursodeoxycholic acid (UDCA) is a bile acid with well-established hepatoprotective, anti-inflammatory, and cytoprotective properties. In addition to its conventional use in the treatment of cholestatic liver diseases, recent evidence has highlighted its potential in dermatological applications. The aim of this study was to develop lipid-based nanoparticles for the topical delivery of UDCA to enhance its therapeutic efficacy in inflammatory skin conditions. The nanoparticles obtained were characterized by suitable size and morphology for topical application, along with an UDCA encapsulation efficiency of about 70%. The solid lipid nanoparticles (SLN)- and nanostructured lipid carriers (NLC)-based hydrogel formulations showed favourable occlusive effects, suitable rheological properties and released UDCA in a controlled manner over 24 h. Both nanoparticle formulations preserved the antioxidant activity of UDCA, while NLC-UDCA showed a statistically significant improvement over free UDCA. Lipid-based nanoparticles may represent a promising platform for the topical delivery of UDCA, warranting further investigation to assess their potential for improving local drug delivery and therapeutic outcomes. Our results highlight the potential of SLN- and NLC-based formulations as a practical and scalable therapeutic approach for dermatological applications, supporting their future pre-clinical development for inflammatory and stress-related skin disorders.
We used simulated data based on Finite Time Pharmacokinetics (FTPK) models to examine the relationship between the peak blood concentration and the fraction of dose absorbed. We also analyzed literature experimental data with top-down FTPK models. The analysis of the simulated data revealed that the peak blood drug concentration is proportional to the fraction of dose absorbed minus the drug eliminated from zero time up to the end of the absorption process. The analysis of literature experimental data provided reliable estimates for the number of input stages, their duration and their input rates. The top-down FTPK models can reliably guide the early phase of drug development. The estimate for the blood concentration value corresponding to the fraction of dose absorbed over the volume of drug distribution, FD/Vd, derived from the fitting of FTPK models to experimental data, is the ideal parameter for the assessment of the extent of absorption. The peak blood concentration value can also be used, although it is not ideal, as a metric of the extent of absorption rather than as a routinely used rate metric.
A major recent breakthrough in the treatment of type 2 diabetes has been the development of glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, current translational frameworks struggle to predict the clinical outcomes of these drugs from preclinical data. Several challenges contribute to this struggle and are relevant to many drugs: GLP-1RAs act through multi-timescale mechanisms in which short-term effects propagate into long-term changes, no single preclinical system can capture all their effects in humans, and mechanistic extrapolation requires modelling numerous whole-body biological processes. To address this gap, we present a new extrapolation approach, M4 drug discovery, and retrospectively apply it to the GLP-1RA exenatide in a manner that is generalisable to other drugs. The method integrates: multi-level data (cellular to whole-body), multi-timescale data (minutes to months), multi-species data (e.g., rodents to humans), and mechanistic knowledge. In this study, we integrate human cell and animal data with drug-free human studies to successfully predict human pharmacokinetics (cost < χ², p=0.05; 64 < 97) and the outcomes of a 30-week clinical trial (36 < 45). We found that integrating information across the four M4 axes improved predictive performance and physiological relevance: multi-species data inform pharmacokinetics, human cell data provide human population- and donor-specific potency estimates, animal data reveal additional drug effects not observable in cell cultures, and the multi-timescale mathematical modelling enables short-term effects of exenatide and meals to inform long-term changes in insulin sensitivity. This work provides a new framework for translational drug development, supporting safer and more informed preclinical-to-clinical translation.
Lung cancer comprises two major histological subtypes, non-small cell lung cancer (NSCLC), which accounts for approximately 80-85% of cases, and small cell lung cancer (SCLC), representing 15-20%; this review discusses the theranostic potential of gold nanostars across both subtypes, with particular emphasis on NSCLC. Despite major improvements in surgery, chemotherapy, radiotherapy, and immunotherapy, therapeutic success remains limited by tumor heterogeneity, drug resistance, and the lack of reliable early detection biomarkers. Therefore, nanotechnology-based strategies are being explored as potential approaches for precision oncology. Gold nanostars have attracted considerable interest because of their anisotropic morphology, tunable localized surface plasmon resonance, and efficient photothermal conversion. In this review, we summarize the structural features, synthesis strategies, physicochemical properties, and emerging applications of gold nanostars in lung cancer diagnosis and therapy. Their plasmonic properties enable integration with imaging approaches, including surface-enhanced Raman spectroscopy, photoacoustic imaging, and computed tomography, as well as therapeutic modalities such as photothermal therapy, photodynamic therapy, and gene delivery. Surface functionalization may further enhance cellular uptake, targeting specificity, and therapeutic performance in selected experimental models. However, the available preclinical evidence remains heterogeneous, with outcomes influenced by nanostar size, morphology, surface chemistry, targeting strategy, administration route, and experimental model. Although several studies report enhanced tumor visualization or therapeutic responses, biodistribution remains variable, and a substantial fraction of administered nanoparticles may accumulate in organs such as the liver and spleen. Moreover, limited standardized head-to-head comparisons and insufficient long-term safety and clearance data prevent definitive conclusions regarding their overall superiority or clinical effectiveness. Gold nanostars therefore represent a promising but still investigational theranostic platform for lung cancer, with further standardized preclinical evaluation, long-term safety assessment, reproducible manufacturing, and well-designed clinical studies required to establish their translational potential.
PURPOSE:Pancreatic cancer is characterized by high malignancy and diagnostic challenges. Plectin-1 is a specific biomarker significantly overexpressed in pancreatic ductal adenocarcinoma (PDAC). This study aimed to synthesize a Plectin-1-targeting radiotracer, 68Ga-DOTA-PLE, and evaluate its potential for pancreatic cancer imaging. METHODS:The precursor DOTA-PLE was radiolabeled with 68Ga, followed by radiochemical yield and stability evaluated. In vitro binding affinity and in vivo biological properties were evaluated using cell binding assays, pharmacokinetic analysis, biodistribution studies, and micro-PET/MR imaging in Plectin-1-positive BxPC-3 and Plectin-1-negative β-TC-6 models. RESULTS:Radiochemical analysis by radio-HPLC and TLC confirmed that ⁶⁸Ga-DOTA-PLE was obtained with high radiochemical purity with no detectable free ⁶⁸Ga or colloidal species. The tracer demonstrated excellent in vitro stability, maintaining a radiochemical purity (RCP) of > 90% after incubation in PBS and serum at 37 °C for 2 h. In vitro binding assays revealed specific binding of ⁶⁸Ga-DOTA-PLE to Plectin-1, as evidenced by significantly higher uptake in Plectin-1-positive BxPC-3 cells than in Plectin-1-negative β-TC-6 cells (P<0.001). Pharmacokinetic evaluation indicated rapid blood clearance, with distribution (T₁/₂α) and elimination (T₁/₂β) half-lives of 2.99 min and 18.99 min, respectively. Biodistribution studies performed prominent tumor accumulation (4.41 ± 1.05%ID/g) at 30 min post-injection. while the radiotracer was primarily excreted via the renal pathway (8.65 ± 1.61%ID/g), exhibiting low hepatic and intestinal background. Micro-PET/MR imaging clearly delineated tumor lesions, and identified 15-30 min post-injection as the optimal imaging window, during which the tumor-to-muscle (T/M) ratio reached its maximum (2.91 ± 0.38).
KRAS-G12D has long been regarded as an intractable therapeutic target due to the flat binding pocket and its strong affinity for GTP/GDP. Proteolysis-targeting chimera (PROTAC) is a revolutionary drug discovery strategy that, by virtue of its unique pharmacological mode of action, provides more options for targeting undruggable targets. In this study, we designed and synthesized 20 novel KRAS G12D PROTACs based on the MRTX1133 derivative. Through systematic exploration of linker structure-activity relationship and multi-cell line screening, compound VI-1 exhibited significant KRAS G12D degradation activity in PANC-0203 cells, achieving 69% effective degradation at 10 μM. Notably, the preferred compounds exhibited significant selectivity for other KRAS mutations and normal cells. This work provides an important lead compound for developing highly selective KRAS G12D PROTACs and warrants further exploration in the context of drug-likeness optimization.
BACKGROUND:Aspirin remains the cornerstone of antiplatelet therapy for acute myocardial infarction (AMI); however, its use is limited in patients with aspirin intolerance, hypersensitivity, or high bleeding risk. Indobufen, a reversible cyclooxygenase-1 inhibitor, has emerged as a potential alternative, yet its cardioprotective effects beyond platelet inhibition and the underlying mechanisms remain incompletely understood. METHODS:Clinical serum samples were collected from patients with ST-segment elevation myocardial infarction (STEMI) receiving aspirin or indobufen therapy. In parallel, myocardial infarction was induced in mice by left anterior descending coronary artery ligation, and neonatal rat cardiac fibroblasts (NRCFs) were subjected to hypoxia in vitro. Cardiac function, fibrosis, autophagy, apoptosis, and oxidative stress were evaluated using echocardiography, histology, immunostaining, western blotting, and transmission electron microscopy. Publicly available single-cell RNA sequencing data were analyzed to explore relevant cellular pathways. RESULTS:In STEMI patients, indobufen treatment was associated with lower circulating levels of cardiac troponin I, thromboxane B₂, IL-1β, and IL-12, along with increased IL-10 levels than aspirin treatment, and these associations remained significant after multivariable adjustment for baseline clinical characteristics. In vivo, indobufen improved cardiac function and attenuated myocardial fibrosis, accompanied by modulation of autophagy-related signaling, reduced apoptosis, and alleviation of oxidative stress. In vitro, indobufen attenuated hypoxia-induced cardiac fibroblast activation, apoptosis, and mitochondrial dysfunction, whereas aspirin exerted limited effects under the same conditions. Mechanistically, indobufen was associated with increased activation of AKT and AMPK signaling pathways and coordinated modulation of autophagy-related proteins. Further pharmacological inhibition of AMPK partially attenuated the autophagy-related effects of indobufen, suggesting that AMPK signaling contributes, at least in part, to the cytoprotective effects of indobufen. CONCLUSIONS:These findings suggest that indobufen may exert myocardial protective effects beyond platelet inhibition, potentially through AKT/AMPK-associated regulation of autophagy, apoptosis, and fibroblast activation. These findings provide a rationale for further investigation of indobufen as a potential alternative antiplatelet strategy in myocardial infarction.
Corallopyronin A (CorA) depletes essential Wolbachia endosymbionts of filarial nematodes and is therefore a promising candidate for treating the neglected tropical diseases lymphatic filariasis and onchocerciasis. To optimize anti-Wolbachia therapy, the pharmacokinetic/pharmacodynamic (PK/PD) relationship was investigated. Due to the intra-nematode and -cellular target, conventional minimal inhibitory concentration could not be determined. Instead, an iterative approach was used to define PD efficacy thresholds and compare them with IC₅₀/IC₉₀ values from infected cells. A physiologically based biopharmaceutics model (PBBM) was developed in GastroPlus®, incorporating physicochemical in vitro and in vivo parameters to predict PK in mice. A mechanistic dissolution model for a CorA-povidone suspension was implemented and verified with in vivo single dose PK data. Simulations provided trough and peak concentrations (Cmax), AUC and time above threshold for multiple dosing regimens. In vivo efficacy was assessed in a Litomosoides sigmodontis mouse infection model by quantifying Wolbachia burden. CorA showed potent in vitro activity (IC₅₀/ IC₉₀: 0.007/0.030 µg/mL). In vivo, fractionated dosing improved efficacy. Cmax poorly predicted treatment outcome, while trough concentration and AUC over iterative model dependent efficacy threshold correlated strongly with the Wolbachia reduction (R²: 0.89 and 0.81). These thresholds show strong concordance with the experimentally determined IC₅₀/IC₉₀ values. The duration of drug exposure above 2.25 µg/mL was the most accurate predictor of efficacy (R²: 0.93). Based on the PK/PD modeling, an effective mouse dose of 16 mg/kg BID was identified. These findings highlight the importance of sustained drug exposure for optimizing CorA regimens and will guide clinical development.
Excipients with a dominating or substantial elastic recovery are characterised by a convex curvature in contrast to the linear association observed for inorganic materials or organic monomers. A model is proposed combining two synchronous processes, a positive linear effect, representing the increase in strength with pressure and a curved component characterising the adverse effect of elastic expansion. Three models are investigated where the negative elastic effect is either exponential (exp(P)), power-function (xP) or a simple quadratic form (P2). The three models are evaluated on their fitness ability, internal correlation and relation between parameters and elastic recovery. The elementary polynomial model, TS = aP - b*P2 + c was preferred due to fitness ability and simplicity in calculation. Furthermore a noteworthy linear relationship was observed between the elastic recovery of tablets from 8 polymer materials and a combination of the linear coefficient a and the quadratic coefficient b as b/a2.For brittle materials, like lactose or dicalcium phosphate without significant elastic deformation, the equation reduces to a straight line.
Phenotypic switching of vascular smooth muscle cells (VSMCs), leading to neointima formation, is a main cause of in-stent restenosis after coronary stent implantation, resulting in poor patient prognosis. Inhibition of VSMC proliferation, migration, and synthetic phenotype transition holds promise for preventing and treating neointimal hyperplasia and restenosis. GW0742, a peroxisome proliferator-activated receptor (PPAR)-β/δ agonist, has been reported to suppress atherosclerosis and myocardial ischemia-reperfusion injury. However, its role in neointima formation has not been previously studied. In this study, we found that GW0742 significantly inhibited carotid artery injury-induced neointimal hyperplasia in mice. In vitro experiments including cell counting, EdU staining, and proliferation marker detection revealed that GW0742 markedly suppressed Platelet-derived growth factor-BB (PDGF-BB)-induced proliferation of human aortic smooth muscle cells (HASMCs). Flow cytometry analysis showed that GW0742 treatment arrested cells in the G2/M phase. Transwell assays demonstrated that GW0742 inhibited HASMCs migration. Moreover, GW0742 reduced the expression of migration-associated proteins matrix metalloproteinases 2 (MMP2) and matrix metalloproteinases 9 (MMP9), while increasing contractile markers alpha-smooth muscle actin (α-SMA) and calponin 1 (CNN1), suggesting that GW0742 suppresses HASMC proliferation, migration, and phenotypic switching, thereby preserving the contractile phenotype. RNA sequencing revealed that GW0742 regulates fatty acid metabolism by upregulating fatty acid binding protein 3 (FABP3) expression to counteract PDGF-BB-induced VSMC phenotypic switching. Knockdown of FABP3 significantly abrogated the inhibitory effects of GW0742 on VSMC proliferation, migration, and synthetic phenotype transition. Taken together, our findings demonstrate that GW0742 upregulates FABP3 expression, leading to the inhibition of VSMC proliferation, migration, and phenotypic switching, and ultimately suppressing neointima formation. These results underscore the therapeutic potential of GW0742 for the prevention and treatment of vascular restenosis.
Preclinical and clinical studies suggest that cannabidiol (CBD) holds therapeutic promise across a range of indications. However, a major barrier to realizing CBD's full therapeutic potential is its inherently low oral bioavailability, partly due to its poor aqueous solubility. To address this, various oral delivery technologies have been explored to enhance the kinetic and apparent solubility of CBD. However, these 'solubilizing' strategies, may inadvertently increase the risk of acid-catalyzed conversion of CBD to tetrahydrocannabinol (THC) in the gastric environment. The possibility of CBD converting to THC in the acidic gastric environment has been debated for many years. Notably, the study by Merrick et al., which reported significant conversion in sodium dodecyl sulfate (SDS)-modified simulated gastric fluid (SGF), raised concerns that oral CBD products might lead to THC intoxication. Yet, other SGF-based studies and human data consistently indicate minimal conversion. We critically revisit the CBD-to-THC literature and discuss the methodological pitfalls associated with using SDS-modified SGF. We propose three conditions required for CBD-to-THC conversion: low pH, CBD accessibility to the acidic environment, and stabilization of the protonated carbocation intermediate essential for ring closure converting CBD to THC. We recommend evaluating micellar CBD formulations containing anionic surfactants like dodecyl sulfate or similar that meet these conditions in acidic SGF. We also discuss the differences between simulated and physiological gastric conditions, including pH, retention time, composition, and dynamic processes, that are likely to limit conversion risk in vivo, although detected in SGF. Overall, our literature review, comparison of human gastric conditions with in vitro SGF models, and our contextualizing of the Merrick et al. study collectively support that concerns about CBD-to-THC conversion in humans remain, at present, a speculative scenario.
BACKGROUND:Lornoxicam (LXM) is a potent non-steroidal anti-inflammatory drug (NSAID), characterised by low aqueous solubility, which limits its oral bioavailability and is frequently associated with gastrointestinal adverse effects. The liquitablet, prepared by blister moulding combined with freeze-drying, was previously shown to significantly improve LXM dissolution. The present study extends that work by comprehensively evaluating biopharmaceutical and pharmacological performance through in vitro permeability testing, cytotoxicity, anti-inflammatory efficacy, and long-term physicochemical stability. METHODS:Dissolution profiling was performed in a pH 1.2 medium. Drug release data were fitted to zero-order, first-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas and Weibull models. Apparent permeability coefficients (Papp) and flux ratios were determined using a horizontal diffusion cell system together with Parallel Artificial Permeability Assays (PAMPA). Cytotoxicity was evaluated using an MTT assay in Caco-2 cells in clinically relevant concentrations. Anti-inflammatory activity was evaluated in Caco-2 cells induced with lipopolysaccharide (LPS) by quantifying the expression of cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) mRNA using polymerase chain reaction (qRT-PCR). Stability was assessed over 12 months at (25°C/60% RH), the assessment focused on drug content, solid‑state characterisation, and dissolution profiling. RESULTS:LXM liquitablets dissolution fitted both Weibull and Korsmeyer-Peppas models, and exhibited a statistically significant increase in Papp compared to pure LXM, with an efflux ratio below 2.0, and maintained Caco-2 cell viability above 70% cytotoxicity threshold at all therapeutic concentrations. It induced a marked downregulation of COX-2 and IL-6 mRNA expression, with high COX-2 attenuation relative to pure LXM, thereby confirming that the liquitablet retains anti-inflammatory activity. Stability data showed no significant changes in drug content (≥ 96%), solid-state characteristics, or dissolution profile. CONCLUSIONS:LXM liquitablets show improved diffusion, biocompatibility, anti-inflammatory action, and long-term stability, providing strong biopharmaceutical support for clinical and regulatory development.
