Medicine and Pharmacology

Abstract: Introduction: Rutin, a glycoside flavonoid that has high neuroprotective efficacy in neurodegenerative diseases, is hindered by low aqueous solubility and poor oral bioavailability. The major challenge in routine delivery is across the blood brain barrier (BBB). So to resolve these problems, in present study we formulate mucoadhesive nano lipid carrier (MNLCs) for intra-nasal administration for the purpose of enhancing residence time in the nasal cavity and targeting in the brain by utilizing trigeminal and olfactory neuronal routes, thus avoiding the BBB. Methodology: MNLCs were prepared by melt emulsification and probe sonication technique and various formulation parameters such as lipid content, surfactant concentration and sonication time were optimized using quality by design (QbD). Results: Box-Behnken design based on particle size, entrapment efficiency and drug release was utilized. Optimized nano-carriers were coated with -cyclodextrin for imparting mucoadhesive properties. Result: The characteristics of nanocarriers showed that the optimized MNLCs have particle size of 150.8 42.5 nm, polydispersity index of 0.592 and zeta potential of -18.2 mV. In vitro release profile demonstrated a sustained release with 80% drug release over 48 h. SEM demonstrated the presence of-cyclodextrin coating on the surface of the nanocarrier. The in vivo studies revealed increased brain delivery and therapeutic effect through nasal administration. Conclusion: All the results indicate that the cyclodextrin coated MNLCs were successful in the delivery of rutin to brain by intra-nasal administration and have shown a sustained release profile with improved bioavailability and neuroprotection.

Abstract: Disproportionality analysis of spontaneous reporting systems is usually used to identify positive signals, meaning drug–event pairs reported more often than expected. The same statistical structure also has a lower-reporting side. A reporting odds ratio (ROR) above unity indicates higher-than-expected reporting, whereas an ROR below unity indicates lower-than-expected reporting. Neither result directly estimates incidence, absolute risk, or causality. Existing critiques of inverse disproportionality signals rightly warn against interpreting ROR < 1 as protection, risk reduction, a beneficial reaction, or therapeutic effect. The same caution applies to ROR > 1. Higher-than-expected reporting is not, by itself, causal evidence of harm. This narrative methodological review argues that positive and inverse disproportionality signals should be interpreted according to the same scientific principles. This does not imply symmetric regulatory action thresholds. In this review, “symmetric scientific standards” means that claims of the same strength require commensurate evidence in both directions; it does not mean identical case-level information, bias mechanisms, detectability, predictive value, regulatory priority, or follow-up procedures. Instead, it calls for interpretation that is consistent with the strength of the claim. To make this approach practical, the review outlines a symmetry check that asks whether critiques of inverse signals also apply to positive signals and whether they address descriptive reporting or causal interpretation. It also proposes a claim-strength framework in which the required evidence depends on the claim being made, not on the direction of the signal. Under this approach, inverse signals may be reported as lower-than-expected reporting. They may also support hypothesis generation or candidate prioritization for follow-up evaluation when robust to comparator and sensitivity analyses. Claims of protection or risk reduction require external validation.

Abstract: Background/Objectives: Drug repurposing is one of the possible sources of new anthelmintics. Afoxolaner is a insecticide/acaricide that acts on the insect GABA receptor and regulates uptake of chloride ions. We examined the interaction of afoxolaner with GABA receptors of nematodes. Methods: We tested the effects of afoxolaner on the motility of the free-living nematode C. elegans and its effect on the contractions/relaxation of the parasitic nematode A. suum. By means of structural bioinformatics, we analyzed the potential binding sites of afoxolaner on the nematode synaptic/exrasynaptic GABA receptor. Results: Afoxolaner inhibited the development of adult C. elegans, significantly reduced the distance traveled, movement speed, and motility score. Afoxolaner significantly inhibited the contractions of the A. suum neuromuscular preparation by increasing the EC₅₀ value of ACh but not changed the E_max. However, afoxolaner neutralized the inhibitory effect of GABA, significantly reduced the EC₅₀ of ACh and increased E_max. In the relaxation study, afoxolaner potentiates GABA-evoked relaxation but inhibited piperazine-induced relaxation. Conclusions: Pharmacological effect of afoxolaner on GABA receptors in nematodes can be defined in two ways: when contractions were induced by ACh, afoxolaner behaves as a partial agonist/antagonist, which would involve binding to an orthosteric site on the receptor. Probably this effect is realized on synaptic GABA receptors between inhibitory interneurons and motoneurons. However, when relaxation is induced by activation of an extrasynaptic GABA receptor, afoxolaner exhibits the characteristics of positive allosteric modulator, it does not cause relaxation by itself, but enhances the effect of GABA and antagonizes the action of piperazine.

Abstract: Theasaponin E2 (TE2) is a triterpenoid saponin isolated from Camellia sinensis seeds with reported anti-inflammatory, antibacterial, and antitumor activities; however, its effects on osteoclasts remain unclear. In this study, TE2 markedly inhibited RANKL-induced osteoclast differentiation in RAW264.7 cells without affecting precursor-cell viability. TE2 also significantly reduced the number and viability of mature, differentiated osteoclasts. Mechanistically, TE2 suppressed RANKL-induced phosphorylation of AKT at Ser473 and GSK-3β at Ser9, as determined by ELISA. Molecular docking predicted that TE2 could interact with the interdomain allosteric pocket of AKT1 at the pleckstrin homology–kinase domain interface (PDB ID: 7NH5; docking score, −9.8 kcal/mol) and the ATP-binding pocket of GSK-3β (PDB ID: 5K5N; docking score, −7.7 kcal/mol). The selected docking poses contained multiple hydrogen-bonding interactions with donor–acceptor distances of 2.79–3.19 Å. Collectively, these findings indicate that TE2 suppresses osteoclast differentiation and reduces mature osteoclast viability, potentially through modulation of the AKT/GSK-3β signaling axis. TE2 may therefore represent a promising natural-product candidate for further investigation in conditions characterized by excessive osteoclast-mediated bone resorption.

Abstract: Oxidative stress is a major driver of chronic disease, making natural polyphenols attractive scaffolds for modulating inflammation, proteostasis, and cell fate. However, green-tea catechins possess a twisted, conformationally flexible flavan-3-ol framework that limits π-conjugation, phenoxyl-radical stabilization, and productive interactions with biological targets. This review presents a structure-based framework in which conformational planarization serves as a strategy for functional amplification. Preorganization of the A/C–B inter-ring bond into a nearly coplanar arrangement reduces the conformational entropy penalty (−TΔS) upon binding or reaction while extending conjugation, strengthening π–π interactions, and facilitating redox reaction. This review highlights planarized catechin (PCat) architectures, including PCat–DTPA (a lesion-activated metal-responsive antioxidant), PCat–TrOH (a self-regenerating antioxidant network), procyanidin B3–PCat hybrids, and a planar silybin analogue, illustrating how planarization and multivalent recognition enhances ROS regulation, inhibits amyloid-β aggregation and neurotoxicity, and suppresses cancer-cell phenotypes. Collectively, these studies establish PCat as a modular platform for the mechanism-informed design of disease-tailored phenolic antioxidants.

Abstract: Background/Objectives: Opiates comprise naturally occurring opium alkaloids and their semisynthetic derivatives. Routine urine drug screening relies on enzyme immunoassays (EIAs) to rapidly detect opiate exposure; however, EIAs provide limited insight into opiate-associated metabolic patterns. Methods: We retrospectively analyzed liquid chromatography quadrupole time-of-flight mass spectrometry (LC-qToF-MS) datasets from comprehensive urine drug screening of 363 patients at the University of Pittsburgh Medical Center Clinical Toxicology Laboratory. Multiple statistical analyses were applied to identify the features associated with opiate (OPIA)-EIA-positive, oxycodone (OXY)-EIA-positive, and 6-monoacetylmorphine (6MAM)-EIA-positive specimens (42, 34, and seven specimens, respectively) designated as EIA-associated discovery feature sets. The feature sets selected by ≥2 statistical analyses were defined as EIA-associated consensus feature set and further evaluated using MS-FINDER for feature annotation. Results: Among 14,883 features, 138, 121, and 104 features were assigned to the OPIA-, OXY-, and 6MAM-EIA discovery feature sets, respectively. Consensus feature sets included oxycodone/opiate metabolites, acetaminophen metabolites, and norfentanyl for OPIA-EIA, oxycodone metabolites, α-phenylalanylaspartic acid, and 4-pyridoxic acid for OXY-EIA, and norfentanyl, 6-monoacetylmorphine, and 3-hydroxycotinine artifact for 6MAM-EIA. Conclusions: These metabolomic patterns indicate a dominant exposure-gradient model, in which OXY-EIA-positive specimens primarily reflect prescribed oxycodone exposure, 6-MAM-EIA-positive specimens reflect illicit heroin/fentanyl exposure with polysubstance/recreational-use signature, and OPIA-EIA-positive specimens occupy an intermediate, mixed profile shaped by immunoassay cross-reactivity and real-world co-exposures. α-phenylalanylaspartic acid may reflect altered amino acid metabolism secondary to chronic opioid exposure. These findings illustrate the value of archived clinical toxicology datasets for metabolomic discovery and as a foundation for sentinel laboratory-based surveillance of evolving drug and chemical exposures.

Abstract: Background: Yokukansan (YKS; Yi-Gan San, TJ-54), a 7-herb Kampo formula, is widely prescribed to ameliorate the behavioral and psychological symptoms of dementia (BPSD), including those arising in Alzheimer's disease (AD). Although YKS improves the behavioral and psychological symptoms of dementia in randomized trials, a compound-resolved map of which YKS constituents act on which BPSD-relevant proteins is still lacking. An integrated network-pharmacology and molecular-docking workflow was applied to predict which YKS constituents act on which BPSD-relevant proteins.Methods: Major constituents of the 7 YKS herbs were retrieved from PubChem. Compound targets were assembled from experimentally measured bioactivities in ChEMBL and BindingDB, and disease-associated targets were obtained from the Open Targets Platform for the 3 behavioral symptom axes of BPSD (psychotic disorder, aggressive behavior and sleep disorder). Common targets were overlaid, a protein-protein interaction (PPI) network was built with STRING, hub targets were ranked by network centrality, and functional enrichment was performed. The 10 highest-ranked hubs by composite centrality were taken forward for docking against all 45 constituents with AutoDock Vina. Predicted compound-target pairs were cross-referenced against known bioactivities to prioritize previously unreported interactions.Results: In total, 45 constituents were mapped to 181 human target genes through measured compound-target edges. Overlaying these on the union of the 3 BPSD symptom bands yielded 37 common targets. The PPI network (37 nodes, 178 edges) identified SRC, MAOB, MAOA, SLC6A4 and DRD1 as principal hubs, and functional enrichment was dominated by the KEGG "Neuroactive ligand-receptor interaction", "Serotonergic synapse" and "Dopaminergic synapse" pathways (all FDR < 0.05). Docking of 45 compounds against the 10 hub targets (450 pairs) gave 424 favorable poses and highlighted the strongest predicted binding at the kinase SRC and the dopamine D4 receptor DRD4, led by brain-penetrant Uncaria alkaloids (e.g., geissoschizine methyl ether, hirsuteine, hirsutine) and Atractylodes terpenoids (atractylenolide I-III). In total, 85 previously unreported compound-target pairs with strong predicted binding were prioritized.Conclusions: A multi-target mechanism is proposed in which YKS constituents jointly engage the central hubs of the BPSD target network, spanning the monoaminergic, kinase-and-enzyme-signaling and adrenergic modules. A centrality-driven selection surfaces action points beyond the serotonergic and dopaminergic receptors that have traditionally defined YKS pharmacology, notably the kinase SRC, the monoamine oxidases MAOA and MAOB and the dopamine D4 receptor DRD4, with SRC and DRD4 showing the strongest predicted binding. The brain-penetrant Uncaria alkaloids (e.g., geissoschizine methyl ether, hirsuteine, hirsutine) and Atractylodes terpenoids (atractylenolide I-III) emerge as the most credible central-acting constituents, so that candidate molecular mechanisms of YKS in BPSD are proposed that extend beyond its conventional monoamine-receptor targets. The prioritized compound-target pairs are offered as specific, testable hypotheses for experimental validation.

Abstract: Synthetic cathinones are a class of new psychoactive substances (NPS) whose structural diversity and rapid evolution complicate toxicological risk assessment. Methylenedioxy cathinones, including methylone, butylone, pentylone and their N,N-dimethyl analogues, occupy a pharmacological space between MDMA-like entactogens and more dopaminergic stimulant cathinones. Although their monoamine transporter profiles and psychostimulant effects have been partially characterized, their direct cardiac liabilities remain poorly understood. Here, we used zebrafish embryos as a multiparametric New Approach Methodology to compare the cardiotoxic and neurobehavioral profiles of methylone, butylone, pentylone, dimethylone, dibutylone, dipentylone, dihexylone and diheptylone. Cardiac rhythmicity was assessed after acute exposure by high-speed video microscopy and dynamic pixel-based analysis, focusing on atrial chronotropy and atrioventricular (AV) conduction. Negative chronotropy increased with alkyl-chain extension, with the monoalkyl subset following the rank order methylone < butylone < pentylone. Among dialkyl analogues, dihexylone and especially diheptylone produced the strongest atrial rate inhibition. AV conduction impairment was more heterogeneous but became prominent among the higher-liability analogues, with diheptylone showing the lowest AV-block EC50 and complete lethality at 1000 µM. Time-resolved locomotor profiling revealed predominantly hypoactive phenotypes, with the most sustained late-phase inhibition observed for dipentylone, dihexylone and diheptylone. Integration of locomotor and cardiac endpoints showed that locomotor effects generally occurred below concentrations producing severe AV conduction impairment, although endpoint separation varied across analogues. Overall, this study provides a structure-oriented zebrafish framework for prioritizing emerging methylenedioxy cathinones with comparatively higher functional cardiac liability.

Abstract: Background/Objectives: Programmed cell death protein 1 (PD-1) is a key immune checkpoint that suppresses anti-tumor T cell responses and is an established target for cancer immunotherapy. UDIZ-007 is a fully human anti-PD-1 antibody that blocks PD-1/PD-L1 and PD-1/PD-L2 interactions and eradicates MC38-hPD-L1 colon tumors in B-hPD-1 transgenic mice. This study further characterized the pharmacokinetics (PK), immunogenicity, and safety of UDIZ-007 to support its clinical development. Methods: UDIZ-007 was produced in a stable Chinese hamster ovary (CHO) cell line, and its biophysical and in vitro functional profiles were assessed. PK, immunogenicity, and safety were evaluated in mice and cynomolgus macaques. Results: UDIZ-007 showed biophysical and in vitro functional properties consistent with therapeutic antibodies and demonstrated potent, dose-dependent anti-tumor activity against MC38-hPD-L1 colon tumors engrafted in B-hPD-1 transgenic mice. Single-dose PK studies in mice at 10 and 100 mg/kg and in cynomolgus macaques at 10, 50, and 101.2 mg/kg showed dose-proportional exposure. In cynomolgus macaques, UDIZ-007 had a prolonged half-life of approximately 12 days. Repeated intravenous administration at 10, 50, or 101.2 mg/kg in cynomolgus macaques was generally well tolerated, with no major treatment-related toxicities. Accordingly, the no-observed-adverse-effect level (NOAEL) was established at the highest tested dose, 101.2 mg/kg. Anti-drug antibodies (ADAs) were detected in some animals and were associated with expected PK variability but not with adverse effects. Tissue cross-reactivity studies across 32 human and cynomolgus macaque tissues showed binding primarily restricted to lymphoid tissues known to express PD-1. Conclusions: UDIZ-007 demonstrated robust anti-tumor activity, favorable PK and safety profiles, as well as selective binding to PD-1-expressing tissues, supporting its clinical development as a potential cancer immunotherapy.

Abstract: Oral targeted therapies now constitute a substantial and growing share of the anticancer armamentarium, shifting drug administration from the controlled intravenous setting to the patient’s home, where systemic exposure becomes contingent on factors that parenteral therapy largely bypasses. Absorption variability, food effects, gastric pH, first-pass metabolism, transporter activity, organ function, concomitant medications, and adherence each contribute to interpatient and intrapatient variability in exposure, and many oral anticancer agents possess narrow therapeutic indices in which modest exposure changes carry clinical consequence. This review synthesizes the pharmacokinetic determinants of oral anticancer drug exposure across twenty-seven exemplar agents spanning the major mechanistic classes—tyrosine kinase, cyclin-dependent kinase 4/6, poly(ADP-ribose) polymerase, Bruton tyrosine kinase, B-cell lymphoma 2, BRAF/MEK, ALK, mTOR, and androgen-axis inhibitors—and translates them into actionable pharmacy practice. We examine the physicochemical and physiological basis of food effects, distinguishing agents that require fasting administration from those that should be taken with food and those with flexible dosing. We address the often underappreciated interaction between acid-suppressive therapy and pH-dependent agents, the dominant role of cytochrome P450 3A4 and the efflux transporters P-glycoprotein and breast cancer resistance protein in mediating drug–drug interactions, and the exposure–response and exposure–toxicity relationships that motivate emerging therapeutic drug monitoring. We highlight several agents whose pharmacokinetic profile diverges sharply from class expectations—including the contrasting acid-suppression sensitivity of acalabrutinib versus ibrutinib, and the perpetrator role of enzalutamide and apalutamide as strong CYP3A4 inducers—and we consider special populations in whom altered pharmacokinetics necessitate individualized management. Synthesizing this evidence, we propose a structured framework through which oncology pharmacists can operationalize pharmacokinetic principles—encompassing interaction screening, meal-timing counseling, acid-suppression review, organ-function assessment, and toxicity monitoring—to optimize the safety and effectiveness of oral anticancer therapy within a precision medicine paradigm.

Abstract: Background: Contrast media are essential tools in diagnostic and interventional imaging, but their relationship with acute kidney injury remains clinically relevant and conceptu-ally debated. This narrative review aimed to synthesize current evidence on contrast me-dia-associated nephrotoxicity, including terminology, epidemiology, pathophysiology, risk stratification, prevention, pharmacotherapeutic management, and clinical deci-sion-making. Methods: A structured literature search was conducted in major biomedical databases and complemented by international guidelines and consensus statements ad-dressing contrast-associated and contrast-induced acute kidney injury in adults exposed to intravascular contrast media. Discussion: Contemporary evidence emphasizes the dis-tinction between contrast-associated acute kidney injury, which reflects a temporal asso-ciation after exposure, and contrast-induced acute kidney injury, which implies causality. The renal risk directly attributable to modern intravenous iodinated contrast media ap-pears to have been historically overestimated, although clinically relevant risk persists in vulnerable patients. Proposed mechanisms include renal vasoconstriction, medullary hy-poxia, oxidative stress, mitochondrial dysfunction, tubular epithelial injury, endothelial dysfunction, and inflammatory or apoptotic pathways. Preventive strategies should be in-dividualized, with isotonic saline remaining the main intervention when indicated, whereas routine pharmacologic prophylaxis is not supported by consistent clinically meaningful benefit. Conclusions: Renal safety in contrast-enhanced imaging requires a balanced approach that minimizes avoidable kidney injury in high-risk patients without unnecessarily delaying clinically indicated diagnostic or therapeutic procedures.

Abstract: Gonadotropin-releasing hormone receptor (GnRHR) agonists are widely used therapeutically, yet their adverse event profile remains insufficiently characterized. We developed a machine-learning model using Tox21 GnRHR agonist activity data and molecular descriptors to predict GnRHR agonist activity among FDA Adverse Event Reporting System (FAERS)-listed drugs. BalancedRandomForest achieved the highest ROC-AUC (0.810) and was applied to 5,523 FAERS-listed drugs. Following applicability-domain assessment, 1,191 drugs were retained, of which 367 were predicted to have GnRHR agonist activity. FAERS data from 2004 Q1 through 2024 Q3 were analyzed using reporting odds ratios (RORs) and Fisher's exact test for MedDRA Preferred Terms (PTs). Overall, 531 PTs met prespecified criteria: at least 1,000 reports, ln(ROR) >1, and p < 0.05. The highest proportions of significant PTs were observed in Respiratory, thoracic and mediastinal disorders; Infections and infestations; and Hepatobiliary disorders. These findings suggest that drugs predicted to have GnRHR agonist activity may show disproportionate reporting of respiratory, infectious, and hepatobiliary adverse events, although causality cannot be established. This framework may support hypothesis generation and safety signal prioritization during drug development and postmarketing surveillance.

Abstract: Bacterial and fungal skin infection are common in companion animals and often require antimicrobial therapy, contributing to antimicrobial resistance. This study developed shampoos containing red palm oil (RPO) and extracts of Rhinacanthus nasutus (RN), Curcuma longa (CL), Zingiber montanum (ZM), and Zingiber officinale (ZO), which provide antibacterial, antifungal, antioxidant, and anti-inflammatory activities. Extracts were obtained using MAE and were evaluate for phytochemical composition, total phenolic content, antioxidant activity (DPPH assay), anti-inflammatory activity (COX-2 inhibition), and antimicrobial activity. RPO contained high level of vitamin E and β-carotene. Rhinacanthin, curcumin, terpinen-4-ol, and 6-gingerol were the major phytochemical constituents of RN, CL, ZM, and ZO extracts, respectively. All extracts significantly reduced COX-2 expression (p< 0.05) while RN exhibited the strongest antioxidant activity (DPPH IC₅₀ = 15.23 ± 0.53 µg/mL). RN and ZM demonstrated the strongest antibacterial activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MIC = 8 µg/mL, MBC = 8–16 µg/mL). ZO exhibited the strongest antifungal activity against Malassezia pachydermatis and Microsporum gypseum (MIC = 2 µg/mL, MFC = 2 - 16 µg/mL). The developed shampoos, containing RPO and four herbs’ extracts showed suitable pH values, stable viscosity, antibacterial inhibition and antifungal inhibition (p < 0.05).

Abstract: Although machine learning models have exhibited high predictive performance in toxicity prediction, chemically interpreting which local structural features or whole-molecule physicochemical properties contribute to the prediction remains challenging. In this study, we propose a fragment–molecular evidence stacking framework that represents molecules as chemically meaningful fragment graphs and separately learns fragment- and molecular-level evidence. The fragment branch outputs evidence logit derived from local structural information in the fragment graph, whereas the molecular branch outputs evidence logit derived from global molecular descriptors. The final prediction is obtained via leakage-free two-logit linear stacking of these two logits. In a 10-seed production evaluation under Tox21 scaffold splits, linear_stack (the proposed model) exhibited a receiver operating characteristic-area under the curve (ROC-AUC) value statistically comparable to that of current_gate (a feature-based gated fusion baseline) and a numerically higher mean precision-recall-area under the curve (PR-AUC). In contrast, linear_stack significantly improved both ROC-AUC and PR-AUC compared with fragment_only and molecular_only (single-branch baselines that use only the fragment and molecular descriptor branches, respectively). These results indicate that although two-logit linear stacking does not consistently outperform more complex feature-based gating, it maintains competitive predictive performance while explicitly integrating fragment- and molecular-level evidence. The significant improvement over fragment_only suggests that molecular-level evidence provides complementary information to fragment-level evidence. The structural removal of the fragment-level partition coefficient (LogP)/topological polar surface area (TPSA) descriptors degraded performance, demonstrating that even local hydrophobicity and polarity information belonging to the same chemical axes as global molecular LogP/TPSA can provide auxiliary predictive information when represented as local distributions on the fragment graph. The Kolmogorov–Arnold network-style heads were evaluated as branch-level nonlinear approximators but were not required for the final integration layer. Standardized evidence contribution analysis also demonstrated that the reliance on fragment- and molecular-branch evidence varied across endpoints, supporting the interpretation of linear_stack as an explicit evidence integration framework (ffragfmoly=affrag+bfmol+c) rather than a uniformly superior classifier. Overall, this study presents a framework that first separates fragment and molecular evidence and then integrates them through explicit two-logit linear stacking, thereby maintaining competitive predictive performance while enabling direct analysis of the final integration of fragment and molecular evidence.

Abstract: Monosodium glutamate (E621) is a common flavor enhancer in highly processed food. Although it makes food more enjoyable, chronic intake may lead to excitotoxicity in brain areas. The current study investigates histological and biochemical neurodegenerative alterations in the rat hippocampus following E621 administration and evaluates the potential neuroprotective properties of vitamin C (ascorbic acid) against E621-induced adverse effects. Forty adult male albino rats were divided into four groups: control (G1), vitamin C (G2), E621-treated (G3), and E621+vitamin C (G4). All rats received daily oral gavage for 30 days. Hippocampal samples were processed and stained with hematoxylin and eosin (H&E), immunostained for GFAP, synaptophysin (a synaptic protein), and caspase-3, and biochemically analyzed for oxidative markers: Malondialdehyde (MDA) and superoxide dismutase (SOD). G3 exhibited significant neurodegenerative changes, characterized by pyknotic granular cells, cytoplasmic vacuolation, with significantly elevated GFAP, synaptophysin, and caspase-3 immunoreactivity in the dentate gyrus (DG). These structural deficits correlated with elevated MDA levels and reduced SOD levels in G3. In contrast, simultaneous administration of vitamin C with E621 resulted in substantial preservation of neuronal morphology, reduction of caspase 3 immunoreactivity, and a restoration of synaptic vesicle density in G4. E621 induces hippocampal injury by increasing ROS levels and dysregulating GFAP, synaptophysin, and caspase-3. At the same time, vitamin C preserves neuronal integrity and synaptic homeostasis, suggesting its potential role as a protective dietary supplement against brain injury induced by the E621 flavor enhancer.

Abstract: Objective: The purpose of this preliminary study was to evaluate the use of the Zipf-Mandelbrot (ZM) law to mathematically model the percentage occurrence of adverse drug reactions (ADRs), as a function of rank, reported to the US FDA Adverse Event Monitoring System (AMES). Methods: Six commonly used hospital-based medications were examined. Nonlinear curve fitting of the two ZM coefficients was utilized to model the percentage occurrence of ADRs in a hierarchical or rank order for each drug examined. Results: The reported complications and their associated occurrence rates for all six medications were accurately modelled using the ZM law. Those medications which have a greater percentage of reported ADRs within their first ten ranks have a greater negative slope. Furthermore, a natural logarithmic transformation of both the reported FDA data and the predicted values utilizing the ZM law demonstrated a consistent statistically significant near-linear correlation. The ratio of the coefficients of the ZM law, a∙b^-1, was also found to be a potentially useful index which allows for describing and comparing the overall shape of the medication-specific distributions. Conclusions: Based upon this preliminary examination, the ZM law appears to be applicable to the mathematical modeling of US FDA reported ADRs. Additional research to assess and utilize this law for the analysis, economic management, and possible improvement in patient outcome may be warranted.

Abstract: Background/Objectives: Silver nanoparticles (AgNPs) hold great promise for antimicrobial, antiviral, and anticancer applications; however, concerns about their toxicity remain a major barrier to their medical use. This study systematically evaluates the acute oral toxicity of five well-characterized AgNP formulations from the Argovit™ family, which previously showed remarkable biomedical properties. Methods: We determine the median lethal dose (LD50), assess clinical signs, and identify the histopathological alterations in mice following oral administration for each formulation. The LD50 was calculated for AgNPs (metallic silver plus stabilizing agent) and for the complete formulation (including water). Results: All formulations showed exceptionally high LD50 values (86,020–150,535 mg/kg) considering the complete formulation, surpassing those reported for other AgNPs in the literature (typically ≤5,000 mg/kg). Clinical signs and toxicological assessment reveal differences in the response of the AgNPs formulations, but all exhibit extremely low toxicity. Histopathological changes were minimal compared to those caused by other AgNP formulations, even though we used doses several times higher. The estimated human LD50 values for the assessed Argovit AgNPs formulations are 17-30 times higher than those reported for other AgNP formulations in the literature. Conclusions: The remarkably low toxicity found in this work contradicts the prevailing assumption that only biogenically synthesized AgNP are biocompatible, highlighting these synthetic PVP-AgNP formulations as a highly safe alternative. The study suggests that the low LD50 may be due to the peculiar structure of Argovit AgNP formulations, which, according to recent data, consists of Ag cores incorporated into PVP nano- and microgels. A high percentage of rapid elimination of Argovit AgNPs from organisms (>98%) via feces also contributes to low LD50. To our knowledge, the present work is the first to study the LD50 of AgNPs-nanogel systems.

Abstract: Acute pain remains one of the most prevalent and burdensome clinical challenges requiring pharmacological intervention, yet opioids — with their well-documented risks of respiratory depression, addiction, and overdose — remain a cornerstone of moderate-to-severe pain management in the absence of efficacious alternatives. Suzetrigine (VX-548) is a novel preferential inhibitor of the voltage-gated sodium channel isoform Nav1.8, recently approved by the US Food and Drug Administration for the treatment of moderate-to-severe acute pain. Through specific inhibition of Nav1.8, which is expressed predominantly in nociceptive sensory neurons of the peripheral nervous system, suzetrigine offers a mechanistically targeted approach to reduce pain at the level of the primary afferent, bypassing the central nervous system circuitry involved in opioid-associated adverse effects. In this review, we examine both the scientific foundation and clinical utility of suzetrigine, integrating evidence from molecular and structural biology, electrophysiology, preclinical animal models, and Phase II and III randomized controlled clinical trials. We discuss the unique allosteric mechanism by which suzetrigine selectively inhibits Nav1.8 to suppress nociceptor excitability, and review six trials, five of which show evidence demonstrating significant analgesic efficacy relative to placebo, and a favorable safety profile. We discuss key limitations of the current clinical evidence base including modest, and sometimes nonexistent efficacy, albeit at the tested doses. Overall, suzetrigine may serve as a proof-of-concept for the development of other sodium channel isoform-specific modulators as targeted therapeutic intervention for a range of diseases. Moreover, the development of cost-effective alternatives to prescription opioids may have substantial population health benefits. Further study with more varied pain types with longer durations including thoroughly examining sex differences with suzetrigine as a monotherapy (i.e. with no use of “rescue” medications) relative to prescription opioids or nonsteroidal anti-inflammatory drugs (NSAIDs) will provide valuable information that could widely benefit acute pain patients and form a scaffolding to bridge the gap between the well-established preclinical foundation and clinical research to enhance the quality of life of those currently living with chronic pain.

Abstract:

limiting systemic exposure. We assessed whether co-therapy with the selective cyclooxygenase-2 (COX-2) inhibitor etoricoxib and the corticosteroid betamethasone provides antinociceptive and anti-edema activity in complete Freund’s adjuvant–induced arthritis (AIA) in rats. Methods: Male Wistar rats (n = 10/group) were allocated to seven groups: intact, AIA disease control, indomethacin 5 mg/kg, etoricoxib 8 mg/kg, betamethasone 0.022 mg/kg, low-dose combination (4 + 0.011 mg/kg) and full-dose combination (8 + 0.022 mg/kg), administered orally once daily from Day 4 to Day 28. Paw edema, von Frey withdrawal thresholds and clinical arthritis score were assessed longitudinally as area-under-the-curve (AUC). Terminal joint tissues were profiled for cytokines, prostaglandin pathway mediators and immune cell markers. Results: Both combinations reduced edema and improved mechanical thresholds versus disease control. The full-dose combination produced the greatest restoration of integrated mechanical sensitivity and arthritis index, exceeding either monotherapy, consistent with additive activity of two mechanistically complementary agents. The low-dose combination achieved improvements equivalent to full-dose monotherapies, a pattern consistent with a dose-reduction effect. Biomarker shifts indicated attenuated prostaglandin signaling and a pro-resolving cytokine balance, with macrophage-associated markers trending toward intact levels. Conclusions: These findings support further evaluation of etoricoxib–betamethasone co-therapy for acute inflammatory conditions.

Abstract: Long‑acting injectable (LAI) formulations have transformed adherence in several psychiatric conditions, yet no depot antidepressant currently exists. People with major depressive disorder (MDD) remain at risk of accidental overdose from prescribed oral medications, particularly during periods of cognitive impairment or crisis. Artificial intelligence (AI)–driven molecular modelling now enables the design of antidepressant compounds optimised for slow‑release, water‑based depot systems that avoid the fibromas and granulomatous reactions associated with oil‑based injectables. This study outlines an AI‑enabled workflow for generating a novel antidepressant molecule with favourable receptor‑binding properties, low toxicity, and compatibility with biodegradable, aqueous depot carriers. The resulting formulation has the potential to reduce overdose risk, improve adherence, and decrease the burden of frequent GP prescribing.