Medicine and Pharmacology

Abstract: Background. Renal drug elimination is incompletely captured by estimated glomerular filtration rate (eGFR) alone. It reflects filtration, transporter-mediated secretion, passive/active reabsorption, renal blood flow, and sometimes metabolism, so proportional GFR scaling may be inadequate for high-clearance drugs, transporter substrates, and advanced chronic kidney disease (CKD).Objective. This review evaluates the basis, structure, verification, applications, and limitations of mechanistic kidney models for renal drug disposition, emphasizing tubular secretion, reabsorption, CKD adaptation, transporter biomarkers, uremic inhibition, and extracorporeal clearance.Evidence synthesis. Renal clearance cannot always be represented by a single GFR-dependent factor. Adaptive tubular flow and water handling affect passive reabsorption in advanced CKD: absolute fold error for reabsorption-prone compounds was 1.05–1.73 with an adaptive model versus 2.61–7.35 with a non-adaptive, proportionally scaled model at CKD stages 4–5 [1]. Transporter-mediated secretion can decline independently of GFR; uremic solutes inhibiting renal organic anion transporters shifted a tenofovir PBPK model from failing to passing a pre-defined 2-fold acceptance criterion [2]. Endogenous biomarkers offer emerging, independent strategies for estimating renal transporter function: pyridoxic acid has been developed as a population-informed biomarker of OAT1/3 activity for predicting transporter-mediated drug-drug interactions [3], and a separate biomarker-informed model combining estimated secretory clearance and renal blood flow with GFR produced only modest improvements in mean absolute prediction error relative to a regression-based comparator [4] a more cautious result than the pyridoxic acid work alone might suggest, and the two lines of evidence are kept distinct in this review. Simple GFR-based methods can match or exceed PBPK models in some direct comparisons (95.0% vs. 93.1% of observations within a 2-fold error band, 33 drugs), so complexity should track elimination mechanism [5].Conclusions. Mechanistic kidney models distinguish filtration, secretion, and reabsorption and incorporate disease-related physiological change, with greatest value for high renal extraction, substantial transporter secretion, nonlinear handling, or marked CKD uncertainty. Progress requires better transporter, biomarker, and extracorporeal-clearance data and standardized verification criteria; mechanistic modelling should complement, not replace, GFR-based approaches.

Abstract: Lutetium Lu 177 vipivotide tetraxetan (177Lu-PSMA-617; Pluvicto, Novartis) is a small-molecule, prostate-specific membrane antigen (PSMA)-targeted radioligand that has redefined the treatment of metastatic castration-resistant prostate cancer (mCRPC) and, following the 2026 approval based on the PSMAddition trial, hormone-sensitive disease as well. Despite its clinical success, the agent's pharmacokinetics as a small, rapidly cleared molecule impose real limits: short tumor residence time, off-target accumulation in the salivary glands, kidneys, and bone marrow, and heterogeneous efficacy in patients with low or discordant PSMA expression. Nanoparticle (NP) engineering has emerged as a complementary strategy to address these constraints by prolonging circulation time, increasing tumor-selective payload delivery through active PSMA targeting and passive enhanced permeability and retention (EPR) effects, enabling multimodal theranostic function, and offering routes to radioprotect healthy tissue. This review synthesizes preclinical and clinical literature (2019-2026) on nanoparticle platforms intersecting with PSMA-targeted radioligand therapy, including gold nanoparticles, polyamidoamine (PAMAM) dendrimers, liposomes and lipid nanoparticles, polymeric micelles, and iron oxide nanoparticles. We describe how these platforms have been used for radionuclide labeling, combinatorial drug delivery, and multimodal imaging, and we summarize the clinical trial evidence for 177Lu-PSMA-617 itself (VISION, TheraP, PSMAfore, PSMAddition) to contextualize the toxicity and efficacy gaps that nanomedicine approaches are designed to close. We conclude by outlining translational barriers -- reproducible manufacturing, comparative organ-level dosimetry, and regulatory pathways for radiolabeled nanomedicines -- that must be resolved before nanoparticle-Pluvicto hybrids can reach the clinic.

Abstract: Octodrine (2-amino-6-methylheptane; DMHA) is a sympathomimetic stimulant detected in sports-performance and weight-loss supplements despite limited toxicological characterization and regulatory concerns. Here, we used 7-day-post-fertilization zebrafish larvae to characterize the acute cardiac, neurobehavioral, and transcriptional effects of octodrine after 2 h of exposure. Cardiac responses were biphasic: 5 µM octodrine significantly increased atrial and ventricular rates, whereas concentrations ≥150 µM produced progressive cardiac depression and higher concentrations disrupted atrioventricular conduction. Exposure to 450 µM resulted in 100% lethality. Nonlinear concentration–response analysis yielded EC50 values of 194.8 µM for atrial rate and 187.9 µM for ventricular rate. At substantially lower concentrations, octodrine significantly reduced spontaneous locomotor activity, with effects detectable at 50 nM and more sustained hypoactivity at 0.5 and 5 µM across most of the 2 h exposure period. At the transcriptional level, exposure to 3.5 µM suppressed several neuronal activity–responsive genes, including fosab, egr1, and npas4a, while nr4a1 was downregulated at higher concentrations. The stress-responsive glucocorticoid target fkbp5 was induced at selected concentrations, whereas th1 and kcnh2a expression was not significantly altered. Together, these findings reveal a marked separation between low-concentration neurobehavioral and transcriptional effects and overt cardiac toxicity at substantially higher concentrations. The results provide an initial in vivo toxicological profile of octodrine and support further investigation of its neuropharmacological mechanisms, internal exposure, and cardiovascular safety.

Abstract: Aging induces profound physiological changes that alter drug disposition and response, narrowing therapeutic windows and increasing susceptibility to adverse drug reactions (ADRs). This review synthesizes current evidence on age-related pharmacokinetic and pharmacodynamic changes, with a focus on pharmacogenomic determinants of drug response in older adults. Progressive decline in renal function, hepatic metabolic capacity, and alterations in body composition collectively necessitate age-appropriate dose adjustments. Polypharmacy, prevalent in community-dwelling and hospitalized older adults, compounds these challenges through drug–drug and drug–drug–gene interactions. Pharmacogenomic testing—particularly for CYP2D6, CYP2C19, CYP2C9, and SLCO1B1—offers a promising strategy to personalize therapy, while deprescribing frameworks provide practical approaches to mitigate medication-related risks. This review presents a comprehensive framework for understanding the mechanistic basis of altered drug response in older adults and proposes actionable strategies for optimizing pharmacotherapy in this vulnerable population.

Abstract: Osteosarcoma is an aggressive primary bone malignancy affecting both humans and dogs, and canine osteosarcoma represents a valuable comparative model for investigating novel therapeutic strategies. Targeting tumour metabolism may enhance the efficacy of existing anticancer treatments. This study investigated whether the mitochondrial uncoupler BAM15 sensitises canine D17 osteosarcoma cells to regorafenib. Cells were treated with BAM15 (20 µM) or regorafenib (REG; IC25, 8 µM; IC50, 16 µM) alone or pretreated with BAM15 before regorafenib exposure. Treatment effects were assessed using viability assays, Annexin V/propidium iodide staining, cell-cycle analysis, Seahorse XF bioenergetic profiling, quantitative PCR, and Western blotting. BAM15 alone was not cytotoxic but significantly enhanced the regorafenib-induced reduction in cell viability at IC50, whereas no significant sensitising effect occurred at IC25. Combined treatment at IC50 increased late apoptotic and necrotic populations and disrupted cell-cycle distribution. BAM15 reduced oxidative phosphorylation-derived ATP production without detectable glycolytic compensation but did not further suppress mitochondrial ATP production beyond regorafenib alone. Combined treatment also induced transcriptional changes in stress-adaptation-related genes, while protein analysis revealed reduced BAX and BAX/BCL-2 ratio. These findings provide preliminary evidence that mitochondrial uncoupling may modify osteosarcoma responses to regorafenib and warrant further mechanistic validation.

Abstract: Pain in children remains frequently underrecognized and undertreated despite significant advances in pediatric analgesia. The pharmacologic management of pediatric pain is challenging due to developmental differences in pharmacokinetics and pharmacodynamics, variability in drug metabolism, age-dependent responses, and the limited availability of high-quality pediatric clinical trials. This narrative review summarizes current evidence regarding the pharmacologic management of nociceptive, neuropathic, and nociplastic pain in children, integrating developmental pharmacology, efficacy data, safety considerations, and limitations of available evidence. A mechanism-based classification of pain provides a useful framework for therapeutic decision-making; however, clinical conditions often involve overlapping mechanisms requiring individualized and multidisciplinary approaches. Evidence supporting pharmacological interventions varies considerably according to pain type. Acetaminophen and NSAIDs remain the most commonly used agents for nociceptive pain, while opioids retain a role in selected cases of moderate-to-severe pain under careful monitoring. Management of neuropathic and nociplastic pain remains particularly challenging due to limited pediatric trials, frequent off-label prescribing, and reliance on extrapolation from adult populations. Future research should focus on age-specific randomized controlled trials, pharmacokinetic and pharmacogenomic variability, long-term safety outcomes, and integration of pharmacologic treatments within multimodal pain management strategies.

Abstract: Background: There is no generally accepted, routine screening for bladder cancer (BC), which is among the ten most common malignancies in men and the most expensive cancer to treat. We examined possibility of using the urinary metabolite concentration 1-Hydroxypyrene (1-OHP) for screening high-risk male individuals for BC. Methods: This was a clinical controlled study. Numerical data were arithmetic mean with standard deviation or median with interquartile range, while categorical data were shown as percentages. Two independent samples were compared by Student t-test or Mann-Whitney U test, depending on the data distribution. Normality was evaluated by Shapiro-Wilk test and box plots. The analysis was performed in the statistical software IBM SPSS ver. 31. Results: This study comprised 117 urinary BC male patients and 110 healthy male controls. The mean urinary values of 1-OHP at first measurement – in patients 205.0 pg/ml (IQR = 116.5-456.5) and in controls 136.5 pg/ml (IQR =76-374.5) with statistically higher values in urinary BC male patients than in controls (p = 0.020). At second measurement – in patients 183.0 pg/ml (IQR = 141.8-407.3) and 137.0 pg/ml (IQR = 73-353.0) with statistically higher values in urinary BC male patients than in controls (p=0.013). Conclusion: 1- OHP values were higher in the BC patients group, but it is not sufficient for urinary screening of high-risk males for BC. We suggest High Performance Liquid Chromatography (HPLC) and Induced Coupled Plasma (ICP) concentration values of urinary biomarkers from other chemical carcinogens incriminated as causes of BC, from Group 1 carcinogens according to the International Agency for Research Cancer (IARC). We reasonably assume that by having urinary biomarker values of chemical carcinogens for BC in men, it would be possible to create an algorithm that could identify men at high risk for developing BC.

Abstract:

Objectives. To identify associations between CYP3A4*22 CYP3A5*3 genotypes, CYP2D6 phenotype and the effectiveness and safety of antipsychotics in neurotypically developed boys with conduct disorders. Methods: The study included neurotypically developed boys aged 7–12 years who were hospitalized for conduct disorders. All patients were prescribed an antipsychotic. Patient follow-up lasted 14 days. Treatment effectiveness was assessed using a clinical aggression assessment (checklist) and the CGI-S, CGI-I, and CGAS scales. Safety was assessed using the UKU SERS and SAS scales. Patients were examined upon enrollment in the study, on day 5, and on day 14. All patients were genotyped for the CYP3A4*22 (rs35599367, C>T), CYP3A5*3 (rs776746, 6986T>C) CYP2D6*3 (rs35742686), CYP2D6*4 (G1846A, rs3892097), CYP2D6*6 (rs5030655), CYP2D6*10 (C100T, rs1065852), CYP2D6*41 (rs28371725) loci. CYP2D6 metabolism type was determined based on genotyping results, and patients were divided into two subgroups: those with normal metabolism (PM) and those with intermediate or poor metabolism (IM+PM). Results: Patients taking carbamazepine (n=11) were excluded from the analysis of associations between treatment outcomes and the CYP3A4*22 and CYP3A5*3 polymorphisms. The analysis of associations between treatment outcomes and CYP2D6 metabolism type was conducted in two stages: the overall sample and a subsample of patients who were prescribed risperidone (n=80). No significant associations were found between carrier status of the CYP3A4*22 and CYP3A5*3 polymorphisms and treatment effectiveness parameters. Analysis of the overall sample did not reveal any significant associations between CYP2D6 metabolism subtypes and the effectiveness parameters of drug therapy. Analysis of patients receiving risperidone revealed one statistically significant association: patients with CYP2D6 IM+PM reported headaches more frequently (16.1% vs 2%; p=0,03). Carrier status of the CYP3A4*22 polymorphism was significantly associated with asthenia and lethargy on day 5 (50% vs. 9.4%; p=0.008). Conclusion: Our study identified only a few significant associations between the CYP3A4*22 polymorphism, CYP2D6 slow metabolism, and patients’ reports of adverse reactions. Further research is needed to identify pharmacogenetic predictors of the efficacy and safety of antipsychotics in neurotypical children with conduct disorders.

Abstract: Synthetic cannabinoids (SCs), marketed as Spice, K₂, and dozens of successor compounds, constitute one of the most pharmacologically dangerous categories of new psychoactive substances (NPS) currently in circulation. Their extreme toxicity relative to Δ⁹-tetrahydrocannabinol (THC) cannot be explained by CB1 receptor pharmacokinetics alone. This review proposes that the purinergic signaling system, specifically the P₂X₇ receptor and the adenosine receptor heteromers A_2A–D₂ and A₁–D₁, constitutes the central molecular amplifier of SC-induced neurotoxicity, operating downstream of CB₁ superagonism but upstream of the neurological phenotypes that define acute SC poisoning. Full CB₁ agonism collapses retrograde synaptic suppression, unleashing glutamatergic excitotoxicity and mitochondrial dysfunction that release massive quantities of extracellular ATP as a damage-associated molecular pattern (DAMP). P₂X₇, acting as the primary cellular sensor of this ATP surge, initiates NLRP3 inflammasome assembly, caspase-1 activation, and IL-1β secretion, establishing a self-sustaining neuroinflammatory cycle in the striatum and cortex. Simultaneously, the ectonucleotidase-mediated conversion of excess ATP to adenosine floods A_2A receptors on striatopallidal neurons, allosterically reducing D₂ receptor affinity for dopamine through the constitutive A_2A–D₂ heterodimer — directly suppressing dopaminergic motor tone and contributing to the psychomotor arrest clinically described as the zombie effect. The A₁–D₁ heteromer in the direct pathway adds a complementary layer of inhibition. Together, these purinergic–dopaminergic molecular interactions translate CB₁ superagonism into the distinctive and dangerous clinical phenomenology of SC intoxication in ways that classical cannabinoid pharmacology does not predict. Pharmacological implications include the potential repositioning of P₂X₇ antagonists and A_2A receptor antagonists as interventions for acute SC poisoning, and the necessity of integrating purinergic endpoints into toxicological profiling of emerging NPS compounds.

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.