Medicine and Pharmacology

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.

Abstract: In pregnancy physiologically based pharmacokinetic (PBPK) modelling within PK-Sim/Mobi, pregnancy stage is canonically parameterised on the fertilisation-age (FA) timescale, yet PK-Sim’s physiology database is indexed by chronological “Age”. The Open Systems Pharmacology (OSP) pregnancy framework therefore encodes FA on a dummy “Age” axis (30.00 years = FA 0 weeks; 30.75 years = FA 38 weeks) and generates pregnancy physiology vectors from FA 0 – 38 weeks discretised at 1-day intervals for database ingestion. Although the anchor points are publicly documented, an explicit closed-form transform and week-resolved lookup suitable for deterministic reproduction of daily physiology grids has not been routinely foregrounded in the literature or repository instructions. A unique affine mapping is derived, implied by the anchors, that provide forward and inverse equations in week- and day-space, quantifying rounding error in terms of FA-day misalignment, and supply a fertilization week (1-38) table for implementation-ready pregnancy virtual population creation in PK-Sim.

Abstract: Background/Objective: Vitamin K (VK) comprises a family of quinone compounds with potential involvement in cell death-related pathways through their redox properties. However, consistent findings have not been obtained regarding the clinical significance of VK in breast cancer (BC). Thus, we used the FDA Adverse Event Reporting System (FAERS) to examine the co-reporting patterns of BC-related adverse-event terms among VK-related reports. Methods: Reporting disproportionality analysis was conducted using FAERS data spanning the first quarter of 2004 to the third quarter of 2024. BC-related reports were defined using all valid Preferred Terms included in the relevant narrow-scope Standardized MedDRA Query (SMQ). Reporting odds ratios (RORs) and proportional reporting ratios were calculated for all VK types and each homolog, followed by exploratory comparisons with other compounds containing quinone structures. Results: In total, 32,156 VK-related reports were identified, including 136 BC-related reports. VK-related reports showed significantly lower reporting disproportionality for breast cancer-related reports (ROR = 0.486, 95% confidence interval = 0.411–0.575). In homolog-specific analyses, similar trends were observed for the quinone-type homologs phytomenadione, menatetrenone, and menadione, whereas no significant reporting disproportionality was detected for the hydroquinone-type homolog menadiol. Conclusions: The differences in reporting patterns among quinone-type VK homologs, hydroquinone-type VK, and other quinone-containing compounds suggest that differences in redox properties may be partially related to the structure of reporting disproportionality. Although this study did not demonstrate causality or clinical efficacy, it provides a hypothesis-generating basis for linking basic, epidemiological, and clinical research using FAERS data. Future validation through mechanistic research and analytical epidemiological studies with stricter control of confounding is warranted.

Abstract: This research explores the aromatase-inhibitory and estrogen-agonistic/antagonistic properties of two natural naphthoquinones, α- and β-lapachone, which are known for their anticancer effects. Initial tests showed that both lapachones inhibit aromatase in the sub-micromolar range, with IC₅₀(β) = 0.78 ± 0.06 μM and IC₅₀(α) = 10.6 ± 2.4μM, similar to the steroidal aromatase inhibitor Exemestane (IC₅₀: 0.02-0.2 μM). A molecular docking study comparing these compounds with androstenedione, one of the native aromatase substrates, identified their binding sites and specific interactions with the enzyme. The Yeast Estrogen Screening assay indicated that both compounds lacked hERα-agonistic activity but exhibited antagonistic effects, similar to 4-Hydroxytamoxifen (Afimoxifene; IC₅₀ = 0.81 ± 0.65 μM). The IC₅₀ values were 0.33 ± 0.24 μM for β-lapachone and 48.3 ± 18.9 μM for α-lapachone. Overall, the study propose unexplored mechanism of action and highlights the dual role of α- and β-lapachones: inhibiting estrogen synthesis and serving as potent, selective estrogen receptor modulators, emphasizing their potential in cancer treatment, especially for hormone-dependent cancers.

Abstract: Background: The adaptogen concept, first formalized over half a century ago, describes pharmacological agents that increase nonspecific resistance to stress. Despite extensive clinical evidence supporting the efficacy of adaptogenic botanicals, the concept has re-mained largely phenomenological, lacking a mechanistic framework compatible with modern molecular pharmacology. This has limited its acceptance in evidence-based medi-cine. Aims: We propose that hydroponically cultivated red Panax ginseng preparation HRG80, with its chemically reproducible composition and multilevel evidence base, constitutes a case study through which the mechanistic basis of adaptogenic action can be examined across molecular, cellular, neurophysiological, and clinical levels. Methods: We identified all published preclinical and clinical studies conducted on HRG80 through PubMed, Scopus, and manual citation tracking (last search: March 2026). Ten published studies met the inclusion criterion, including three randomized, dou-ble-blind, placebo-controlled clinical trials and two open-label trials, encompassing ap-proximately 440 human subjects. One manuscript in preparation and one unpublished preclinical gut-brain axis dataset were included with appropriate caveats. We integrated transcriptomic, electrophysiological, in vitro, in vivo, and clinical evidence into a pro-posed mechanistic model. Results: The converging evidence supports a three-tier temporal model of adaptogenic ac-tion. The acute tier (minutes to hours) involves modulation of NMDA and Kainate gluta-mate receptors, enhancing hippocampal long-term potentiation. The subacute tier (days to weeks) involves activation of CREB signaling and the slit-robo axonal guidance pathway, producing structural neuroplasticity functionally equivalent to brain-derived neu-rotrophic factor stimulation. The chronic tier (weeks to months), based on in vitro evidence in non-neuronal models, involves DNMT inhibition and epigenetic reprogramming, sug-gesting a potential mechanism for durable changes in cellular stress resilience. Tran-scriptomic analysis identified 1,061 genes uniquely modulated by the whole extract and not by isolated ginsenosides, consistent with the hypothesis that the adaptogenic effect is an emergent property of the phytochemical network. Preliminary preclinical data from a gut-brain axis model suggest that HRG80 protects intestinal barrier integrity and attenu-ates neuroinflammation, providing a plausible systemic pathway from oral intake to cen-tral effects. Conclusion: HRG80 provides convergent multilevel evidence suggesting that adaptogenic nonspecificity may reflect a hierarchically organized multi-specificity operating across distinct temporal scales. If confirmed by independent replication and further mechanistic studies, this framework could offer a template for the systematic investigation of other adaptogenic botanicals.

Abstract: Severe cutaneous adverse reactions (SCARs) are rare, life-threatening drug hypersensitivity syndromes. Although pharmacovigilance can identify drugs disproportionately reported with SCARs, it does not reveal which local chemistries recur among them. To address this, we assessed whether drugs with disproportionate SCAR reporting in the FDA Adverse Event Reporting System (FAERS) share interpretable chemical motifs. We screened FAERS data from 2004Q1 to 2024Q3, identified 5523 drugs with available Simplified Molecular-Input Line-Entry System (SMILES) representations, and constructed a signal-enriched dataset of 1676 compounds with nominally significant broad-SCAR associations after excluding predefined therapeutic/supportive confounders. Compounds were assigned to positive-signal [natural logarithm of reporting odds ratio (lnROR) > 0, n = 1219] or nonpositive-signal (lnROR ≤ 0, n = 457) classes and encoded with 9753 explicitly mappable atom-centered local substructure descriptors. A light gradient boosting machine classifier evaluated using repeated nested cross-validation (six-fold outer × 50 repeats) achieved moderate but stable internal discrimination (mean area under the receiver operating characteristic curve = 0.7041 ± 0.0337). SHapley Additive exPlanations (SHAP) analysis revealed a clear fragment-level contrast: allylamine-like, ethanolamine, and diaminopropane-related motifs were associated with higher positive-signal class probability, whereas phenol and pyrimidine motifs were associated with corresponding lower probability. The phenol fragment (Oc1ccccc1) was the most influential feature overall (mean |SHAP| = 0.1727), followed by an allylamine-like fragment (0.1031). These findings suggest that broad-SCAR concern detected in the FAERS is not chemically random within the selected dataset. Overall, the proposed framework should be viewed not as a direct predictor of absolute clinical SCAR risk but as an interpretable structure-guided safety-screening approach to prioritize compounds and motif families for further SCAR-focused evaluation.

Abstract: Background: Oral administration remains the preferred delivery route for supplements and bioactive compounds, yet the mucosal barrier restricts systemic exposure of most therapeutic agents to a small fraction of the administered dose. Enzymatic degradation, pH-dependent instability, and limited paracellular transport collectively constrain bioavailability, particularly for hydrophilic nutrients, peptides, and mineral ions. Framework: This paper proposes a three-mechanism framework to explain how a class of surface-active mineral oxide delivery systems may enhance mucosal absorption through established biological pathways. The framework is grounded entirely in peer-reviewed physiology and pharmacology independent of any proprietary formulation data. Mechanisms: The three proposed mechanisms are: (1) a low-dose, transient reactive oxygen species (ROS) pulse that reversibly modulates tight junction proteins, expanding paracellular permeability within a well-characterized physiological range; (2) surface-mediated delivery of mineral oxide species directly to mucosal epithelial cells, bypassing the portal circulation route that limits conventional oral mineral delivery; and (3) activation of the NRF2-KEAP1-ARE pathway in mucosal cells, upregulating endogenous antioxidant defenses through hormetic adaptation. These mechanisms are supported by the established biology of hormesis, tight junction physiology, mineral pharmacology, and redox signaling. Comparison to Existing Approaches: Liposomal encapsulation protects cargo from gastric degradation but achieves typical oral bioavailability of 1 to 15 percent for peptide cargo and faces instability challenges in the gastrointestinal environment. The mineral oxide delivery approach described here modifies the absorption environment itself rather than encapsulating cargo, representing a mechanistically distinct and potentially complementary strategy. Conclusion: This framework offers a biologically plausible, citation-supported basis for enhanced oral and sublingual delivery of nutrients and peptide compounds. Controlled clinical pharmacokinetic studies are needed to confirm these mechanisms and quantify the magnitude of bioavailability enhancement in human subjects.

Abstract: Background/Objectives: Drug supply disruptions represent an increasingly serious problem for health systems worldwide, with systemic antibiotics among the most frequently affected therapeutic categories. Although regulatory authorities have repeatedly signaled this risk, comparative studies analyzing patterns of antibiotic shortages across multiple countries simultaneously remain scarce. Methods: We performed a cross-sectional comparative analysis based on data from public national shortage registries in seven jurisdictions: Belgium, France, Germany, Romania, Spain, the United States (FDA), and the Kingdom of Saudi Arabia. All records corresponding to systemic antibiotics in ATC group J01 were extracted, harmonized, and analyzed, with the active substance (INN) as the unit of analysis. The association between critical drug status according to the EMA list and the multinational recurrence of shortages was assessed using chi-square tests, the Mann–Whitney U test, and multivariate logistic regression. To verify the robustness of the results, a sensitivity analysis was also performed using alternative thresholds for jurisdictions. Results: A total of 350 shortage records were mapped, corresponding to 64 unique active pharmaceutical ingredients. On average, each active substance was reported as out of stock in 3.48 jurisdictions (SD = 1.46). Macrolides (J01F) and quinolones (J01M) exhibited the widest geographic spread of shortages. Antibiotics included on the EMA’s list of critical medicines were reported as missing in multiple countries simultaneously significantly more frequently than those not included on this list (82.86% vs. 37.14%; χ² = 71.99, p &lt; 0.001; Cramer’s V = 0.454). In the multivariate logistic regression model, EMA critical medicine status remained an independent predictor of multinational recurrence of shortages (OR = 8.29; 95% CI: 4.93–13.94; p &lt; 0.001), while the injectable route of administration did not reach the threshold for statistical significance (OR = 0.78; p = 0.341). Sensitivity analysis confirmed that this association remains statistically significant regardless of the threshold chosen. Conclusions: Shortages of systemic antibiotics tend to occur simultaneously in multiple countries, and drugs designated as critical by the EMA are disproportionately affected. The results suggest that the identified weaknesses are not specific to a single health system but reflect structural fragilities in international antibiotic supply chains. This underscores the need for internationally coordinated strategies, both for monitoring the availability of essential antibiotics and for preventing and managing shortages.