Abstract: This study unveils a new class of spiro[1,2,4]triazolo[1,5-c]quinazoline derivatives as promising diacylglycerol kinase α (DGKα) modulators, a target implicated in cancer, neurological disorders, and immune dysfunction. Through structure-based computational design using the CB-Dock2 platform with human DGKα EF-hand domains (PDB ID: 6IIE), 40 novel compounds were systematically evaluated along established inhibitors (ritanserin, R59022, R59949, BMS502, and (5Z,2E)-CU-3) across five distinct binding pockets. Several compounds demonstrated remarkable binding profiles at the level or surpassing reference compounds. The physicochemical analysis revealed balanced drug-like properties with favorable molecular weights (252-412 g/mol) and appropriate three-dimensionality. Toxicological assessment indicated reassuring safety profiles with predicted LD50 values of 1000-2000 mg/kg and minimal hepatotoxicity, carcinogenicity, and mutagenicity potential. Notably, compound 33 (adamantyl-substituted) emerged as exceptionally promising, exhibiting strong binding affinity, moderate solubility, and selective CYP inhibition patterns that minimize drug-drug interaction risks. Detailed molecular interaction mapping identified critical binding determinants, including strategic hydrogen bonding with TRP151, GLU166, and ARG126. The multidimensional evaluation identified compounds 13, 18, 33, and 40 as particularly promising candidates that balance potent target engagement with favorable pharmaceutical profiles, establishing this scaffold as a valuable platform for developing next-generation therapeutics targeting DGKα-mediated signaling pathways.

Abstract: Background: Quinoline-derived metabolites exhibit notable chemical complexity. What causes minor structural alterations to induce significant changes in disease outcomes? Historically eclipsed by more straightforward scaffolds, these chemicals serve as a dynamic hub in tryptophan metabolism, linking immunomodulation, excitotoxicity, and cancer. However, many of these compounds struggle to cross the blood–brain barrier, and we still do not fully understand how certain structural changes affect their bioavailability or off-target effects. Thus, contemporary research highlights halogenation, esterification, and computational modeling to enhance structure–activity relationships. Summary: This narrative review emphasizes the integration of rational drug design, multi-target ligands, and prodrug methods in enhancing quinoline scaffolds. We explore each molecule’s therapeutic promise, refine each scaffold’s design, and develop each derivative to maximize clinical utility. Translating these laboratory findings into clinical practice, however, remains a formidable challenge. Conclusion: Through the synthesis of findings regarding NMDA receptor antagonism, improved oral bioavailability, and reduced metabolic instability, we demonstrate how single-site changes might modulate excitotoxicity and immunological signaling. Advancing quinoline-based medicines will yield significant advancements in neurology, psychiatry, and oncology. This enlarged framework fosters collaborative discovery, engages various audiences, and advances the field towards next-generation disease-modifying therapies. Robust preclinical validation, patient classification, and comprehensive toxicity evaluations are crucial stages for achieving these extensive endeavors and fostering future therapeutic discoveries globally.

Abstract: Background: Photodynamic therapy (PDT) utilizing nano-based photosensitizers (PS) of-fers promising cancer treatment potential but requires rigorous safety evaluation. Conju-gated polymer nanoparticles (CPNs) doped with porphyrins, such as platinum porphy-rin-doped poly(9,9-dioctylfluorene-alt-benzothiadiazole) (F8BT), exhibit enhanced photo-dynamic efficiency but lack comprehensive preclinical toxicity data. This study aimed to evaluate the biocompatibility, biodistribution, and acute/subacute toxicity of these CPNs to establish their safety profile for clinical translation. Methods: CPNs were synthesized via nanoprecipitation using amphiphilic stabilizers (PSMA or PS-PEG-COOH) and char-acterized for colloidal stability in parenteral solutions. Hemolysis assays assessed blood compatibility. Single-dose (0.3 and 1 mg/kg, intravenous) and repeated-dose (0.1–1 mg/kg, intraperitoneal, every 48 hours for 28 days) toxicity studies were conducted in BALB/c mice. Hematological, biochemical, histopathological, and biodistribution analyses (via ICP-MS) were performed to evaluate systemic and organ-specific effects. Results: CPNs demonstrated excellent colloidal stability in 5% dextrose, with minimal aggregation. No hemolytic activity was observed at concentrations up to 50 mg/L. Single and repeated ad-ministrations revealed no significant changes in body/organ weights, hematological pa-rameters (except transient fibrinogen elevation), or liver/kidney function markers (ALT, AST, BUN, Cr). Histopathology showed preserved tissue architecture in major organs, with mild hepatocyte vacuolation at 30 days. Biodistribution indicated hepatic/splenic accumulation and rapid blood clearance, suggesting hepatobiliary elimination. Conclu-sions: Platinum porphyrin-doped F8BT CPNs exhibited minimal acute and subacute tox-icity, favorable biocompatibility, and no systemic adverse effects in murine models. These findings support their potential as safe PS candidates for PDT. However, chronic toxicity studies are warranted to address long-term organ accumulation and metabolic impacts. This preclinical evaluation provides a critical foundation for advancing CPNs toward clinical applications in oncology.

Abstract: Background/Objectives: Ketamine anesthesia frequently causes postoperative cognitive dysfunction and behavioral disorders, with limited effective therapeutic options. This study explores novel neuroprotective compounds targeting multiple pathways in neurological disorders following ketamine anesthesia through the design, synthesis, and evaluation of 2'-R-6'H-spiro(cycloalkyl-, heterocyclyl)[1,2,4]triazolo[1,5-c]quinazolines. Methods: Using fragment-oriented design, we synthesized 40 spiro-triazoloquinazolines via [5+1]-cyclocondensation. Molecular docking assessed binding affinities to glutamate receptor GluA3, while ADMET analyses evaluated pharmacokinetic properties. Selected compounds were tested in a ketamine-induced cognitive impairment rat model with behavioral assessment via open field test. Neurobiochemical analyses measured inflammatory markers, apoptotic regulators, and gene expression in hippocampal tissue. Results: Molecular docking showed superior binding affinities to GluA3 compared to reference nootropics, while ADMET analyses confirmed favorable drug-likeness profiles. In vivo evaluation demonstrated compounds 25, 26, and 32 effectively normalized ketamine-disrupted behavioral parameters, reducing anxiety and improving cognitive function more effectively than piracetam and fabomotizole. Neurobiochemical analyses revealed compound-specific mechanisms: compound 31 showed potent anti-inflammatory effects (72% reduction in IL-1β, 80% reduction in caspase-1), while compound 26 enhanced cell survival pathways (96% increase in Bcl-2) and hypoxic adaptation (3.5-fold increase in HIF-1 mRNA). Structure-activity relationship analyses established that spiro-junction type and 2'-position substituent critically determine pharmacological profiles. Conclusions: These novel spiro-triazoloquinazolines demonstrate promising neuroprotective properties for treating cognitive and behavioral disorders associated with ketamine anesthesia through multiple mechanisms including anti-inflammatory, anti-apoptotic, and adaptive pathway modulation. Their superior efficacy compared to current treatments positions them as candidates for further development in post-anesthetic cognitive dysfunction and potentially in post-viral and trauma-related neurological conditions.

Abstract: Despite its pivotal role in drug metabolism, the exact consequences of rising medica-tions count from various therapeutic drug classes on mortality outcomes amongst patients with chronic liver disease remains unexplored. In this study, we investigated the effect of different polypharmacy phenotypes on clinical outcomes including the length of hospitalization, the need for intensive care admission, and mortality in patients with chronic liver disease (CLD). Methods: This retrospective cohort study examined the impact of various polypharmacy phenotypes on clinical outcomes of patients receiving care at tertiary care centres within the Weill Cornell Medi-cine-affiliated Hamad Medical Corporation, Doha Qatar diagnosed with CLD be-tween October 2018 to August 2021. Primary outcomes include all-cause mortality, length of hospitalization, and need for intensive care unit admission. Multivariable regression models were used to assess the associations between the number of liv-er-related and non-liver-related polypharmacy and these clinical outcomes. Results: In this retrospective cohort study, 3331 participants with a median age of 50 years (interquartile range [IQR] 40–63) were included, of which 71.0% (n = 2 366) were males. The total duration of follow-up for the whole cohort was 42 772.6 per-son-days. The median length of stay (LOS) was 5.0 (0.5, 13.6) days, with 762 (22.9%) deaths among those hospitalized. About 46.2% of the study participants were on guideline-directed therapy CLD drugs. Patients with polypharmacy inclusive of liver-related drugs had a higher survival over time compared to the group without polypharmacy (log-rank p< 0.001). Each additional CLD drug is associated with a 51% reduction in mortality risk (hazard ratio [HR] 0.49, 95% CI 0.38–0.62). Conclusion: In a hospitalized cohort of patients with CLD, polypharmacy comprising of medications specific for CLD or its complications was associated with reduced all-cause mortality. However, the role of non-liver-related medications in this context remains unclear, and it is uncertain how the primary cause of liver disease could have potentially impacted these outcomes. Further studies exploring these factors are needed to better inform clinical decision-making regarding polypharmacy management in this patient population

Abstract: The purpose of this communication is to clarify criticisms that have arisen in the context of our publication "Methodological Considerations Regarding the Quantification of DNA Impurities in the COVID-19 mRNA Vaccine Comirnaty®" (Methods and Protocols 2024, 7, 41, May 2024 [1]). After an exchange of opinions, a comment was submitted within a Comment and Reply Procedure started by Methods and Protocols by Kaiser and Marschalek [2], in which they assailed our publication. But after reading our reply which we submitted by 24 September 2024, Kaiser and Marschalek decided to submit the data contained in their comment in parallel together with further authors as a regular article to another journal, titled "Quantification of objective concentrations of DNA impurities in mRNA vaccines" (Kaiser et al 2025 [3]), of which an earlier version has been published as a preprint already in November 2024 (Kaiser et al 2024 [4]). This publication and preprint attempted to refute our findings obviously aiming to be published without our resoponse and undermining the Comment and Reply Procedure. However, it does not succeed in doing so with the necessary persuasiveness. First of all, it is particularly important that Kaiser and Marschalek [2] and Kaiser et al [3, 4] have confirmed that our results are reproducible when the quantification is carried out using the Qubit® technology in accordance with the manufacturer's instructions, which is exactly what we did. However, it is then claimed by Kaiser and Maschalek [2] as well as by Kaiser et al [3, 4] that the magnitude of the DNA impurities we have shown would be an effect of high amounts of RNA present in the samples. As a proof they quantified a defined concentration of DNA in the presence of very high concentrations of RNA with the Qubit® methodology. However, even the presence of 250 ng/µL RNA resulted only in a comparatively small increase in the DNA value of 0.655 ng/µL and this is far from explaining the DNA concentrations of 12 to 17.8 ng/µL that we have measured in several batches of Comirnaty®. Further, Kaiser and Marschalek [2] and Kaiser et al [3, 4] mentioned that experiments with DNA extracted from the vaccine would show that the very low legal limits for DNA in Comirnaty® are met. However, the authors of this critique have failed to demonstrate that the extractions they performed are indeed quantitative, i.e. reflect the actual DNA contamination. But, based on the related published literature, this must be denied. With this in mind, we can finally confirm that both our methodology and our data, as published in our above-mentioned article [1], imply that DNA impurities as measured with Qubit® by us in Comirnaty® are reliable according to the manufacturer's premises for this DNA quantification technology. In this sense, the DNA values presented by Kaiser and Marschalek [2] and Kaiser et al. [3, 4] after extraction procedures are obviously artificial effects of the extractions performed and therefore do not represent the true DNA contamination of the concerned Comirnaty® batches. Finally, our data for DNA contaminations in Comirnaty have been confirmed in December 2024 explicitly by research utilizing different Methods which has been conducted in a Labortory of the US Food and Drug Administration FDA [5]. However, this publication has been ignored by Kaiser et al. in their own publication of March 2025 [3] which appeard almost 3 months later and thus should have cited and discussed the particular findings which are confirming our data.

Abstract: Background/ Objective: Major depressive disorder (MDD) is a common mental disorder, with a significant part of patients developing treatment-resistant depression (TRD). Esketamine is an antagonist of the N-methyl-D-aspartate receptor indicated as a nasal spray in combination with other antidepressants for adults with TRD. Signals of suspected adverse reactions (SARs) to esketamine from the EudraVigilance database in European countries were analyzed for a more defined safety profile of this drug in the real-world. Methods: SARs to esketamine reported in the data system EudraVigilance were analyzed and disproportionality analysis for adverse reactions indicating sui-cidality for esketamine, in comparison to the antidepressants fluoxetine and ven-lafaxine, was performed. Results: “Blood pressure increased” (15.4%) and “Dissocia-tion” (15.0%), are the more frequently reported SARs. Sex distribution indicates prevalence of women, except for “Blood pressure increased” and “Completed suicide”, more signaled for men, while adults (18-64 years) and elders (65-85 years) are the ages with the largest number of reported adverse reactions to esketamine. Results show a significant increase of risk of suicide for esketamine, when compared with fluoxetine and venlafaxine. Conclusions: Apart of carefulness due to the known limitations of pharmacovigilance research conducted by using datasystem of spontaneous signals for SARs, analysis of data on points towards the need for greater attention for risk suicide following prescription of esketamine in depressed subjects. In this regard, as well as regulatory agencies recommend, patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to begin treatment, should receive a more careful monitoring during treatment.

Abstract: The C1858T PTPN22 variant is strongly associated with Type 1 diabetes and autoimmune thyroid disease. Current treatment is the substitutive hormonal administration which does not target the disease pathogenetic mechanism. Background/Objectives: We previously implemented a novel immunotherapy, employing siRNA directed against the C1858T variant of PTPN22 delivered via functionalized lipoplexes in order to halt autoimmune disease progression. The objective of this study was to optimize lipoplexes formulations functionalized with F9-PEG (a Siglec-10's ligand) to facilitate targeted delivery, by testing their physical and chemical properties to warrant best performance in in vivo studies. Methods: The effectiveness of siRNA-liposome binding was evaluated by varying the relative lipid/siRNA charge ratio and analyzing the stability of the different formulations with respect to methods of F9-PEG addition and ATTO740 fluorescent labelling by electrophoresis, dynamic and dielectrophoretic light scattering (DLS, DELS), and high-performance liquid chromatography (HPLC). A preliminar investigation of lipoplexes biodistribution was conducted by fluorescent tagging in C57BL/6 mice. Results: The optimal charge ratio of +2 /-1 (lipid/siRNA) ensured greater stability of lipoplexes. Stability was improved by functionalization with F9-PEG further by the addition of ATTO740-dye. HPLC confirmed the integrity of siRNA after preparation. Injection of PKH26-labelled lipoplexes in mice showed selective accumulation in target tissues within 48 hours. Conclusions: The results of this study lead to formulations of F9-PEG lipoplexes with optimal properties that could be used for biodistribution and safety/efficacy studies in mice. Lipoplexes functionalized with F9-PEG could therefore represent a promising personalized nanotherapeutic platform for targeted siRNA delivery in endocrine C1858T patients.

Abstract:

Cystic fibrosis (CF) is a life-threatening disorder caused by mutations in the CFTR gene, leading to defective chloride ion transport and thickened mucus in the respiratory and gastrointestinal systems. CFTR modulators, including ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have improved patient outcomes, but interindividual pharmacokinetic variability and potential drug-drug interactions require therapeutic drug monitoring (TDM) for optimal efficacy and safety. In this context, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simul-taneous quantification of CFTR modulators and their major active metabolites in human plasma to support pharmacokinetic studies and routine TDM. The multiplex LC-MS/MS assay was established using plasma protein precipitation, followed by chromatographic separation on an Xselect HSS T3 column and positive electrospray ionization mode detec-tion. The method was validated based on FDA and EMA guidelines for specificity, linear-ity, accuracy, precision, matrix effects, and stability, demonstrating robust performance with excellent precision and accuracy. International interlaboratory comparisons con-firmed the reliability of the assay. The developed method has been applied for monitoring caftors plasma levels for patient TDM and also to research studies in alternative matrices such as breast milk. Future studies will help at characterizing caftors pharmacokinetic variability in patients and drug-drug interactions to further refine personalized dosing strategies.

Abstract:

Acrylamide (ACR) is a potent neurotoxicant that disrupts cellular redox homeostasis by depleting reduced glutathione (GSH) and inducing oxidative stress. Despite its well-characterized mechanism, effective treatments for ACR-induced neurotoxicity remain elusive. This study evaluates the therapeutic potential of N-acetylcysteine-amide (AD4), a blood-brain barrier-permeable derivative of N-acetylcysteine, in a novel severe acute ACR neurotoxicity model in adult zebrafish. Intraperitoneal administration of a single high dose of ACR (800 mg/kg) resulted in a 51% reduction in brain GSH levels, which was fully rescued by AD4 treatment. Behavioral analyses revealed that ACR exposure impaired short-term habituation of the acoustic startle response (ASR), a deficit that was mitigated by AD4. Surprisingly, ACR exposure did not alter the neurochemical profile of key neurotransmitters or the expression of genes related to redox homeostasis, synaptic vesicle recycling, regeneration, or myelination. These findings highlight the efficacy of AD4 in counteracting ACR-induced oxidative stress and behavioral deficits, underscoring its potential as a therapeutic agent for ACR neurotoxicity. This study also validates the adult zebrafish as a translational model to investigate neurotoxic mechanisms and evaluate neuroprotective interventions.

Abstract:

Pesticides are essential in agriculture for protecting crops and boosting productivity, but their widespread use may pose significant health risks. Farmworkers face direct exposure through skin contact and inhalation, which may lead to hormonal imbalances, neurological disorders, and elevated cancer risks. Moreover, pesticide residues in food and water may affect surrounding communities. One of the lesser investigated issues is immunotoxicity, mostly because chronic effects of compound exposure are very complex to study. As a case study, this work utilized pharmacophore modeling and virtual screening to identify pesticides that may inhibit Janus kinases (JAK1, JAK2, JAK3) and tyrosine kinase 2 (TYK2), which are pivotal in immune response regulation and associated with cancer development and increased infection susceptibility. We identified 64 potential pesticide candidates, 22 of which have previously been detected in the human body, as confirmed by the Human Metabolome Database. These results underscore the critical need for further research into potential immunotoxic and chronic impacts of the respective pesticides on human health.

Abstract: We investigated whether the functional involvement of α1-adrenergic receptors (α1-AR) in the effects induced by antidepressant drugs, desipramine, and milnacipran varies depending on the α1-AR subtype. First, using a mouse line with triple knockout (KO) of genes encoding all three α1-AR subtypes (ABD-KO) and autoradiographic analysis, we demonstrated that the inactivation of α1-AR did not affect the density of other types of adrenergic receptors, α2- and β-AR in the mouse brain. Subsequently, we utilized three mouse knockout lines with selective inactivation of the gene encoding a single α1-adrenergic receptor subtype (A-KO, B-KO, and D-KO). We analyzed the impact of these mutations on tissue levels of monoaminergic neurotransmitters in the hypothalamus. Next, we assessed how a specific mutation affects the long-term effects of desipramine and milnacipran in the selected brain regions of male and female mice at various molecular levels: mRNA expression of α1-AR subtypes, gene expression profiling, and activation of selected signaling proteins (ERK1/2, Akt, GSK3). The main finding is that the inactivation of the α1D subtype modulates at various molecular levels the long-term effects of desipramine or milnacipran in a sex-dependent manner. Our study revealed the functional diversity between α1-AR subtypes in the molecular mechanisms of antidepressants’ drug action.

Abstract: Boron-containing compounds (BCC) have emerged as potential drugs. The effects of letting act as drugs are mainly by means of action on enzymes. Moreover, no crystal structure shows binding to G-Protein coupled receptors (GPCRs), albeit if those are recognized as targets in many diseases. However, some experimental data support the effects of specific BCC on GPCRs. Objective: Updating data about the reported effects that suggest or support interactions of BCC on GPCR. Methods: Data were collected and reviewed from the National Center of Biotechnology Information, PubMed, Global Health, Embase, the Web of Science, and Google Scholar databases. Results: Some experimental reports support the interactions of BCC in several GPCRs, acting as labels, agonists, or antagonists on them. Details of interaction can be inferred by in silico and in vitro results. Albeit if not a crystal structure showing such a complex. Conclusions: The action of BCCs on GPCR is beyond a presumptive proposal. Evidence supports the interaction and actions of BCCs on GPCRs.

Abstract:

Jaspine B, an anhyrophytosphingosine, has potent anticancer properties. However, it exhibits low oral bioavailability, reducing therapeutic effects despite its cytotoxicity. This study aimed to address this issue by improving the pharmacokinetics of Jaspine B through liposomal formulation. Jaspine B liposomes were prepared using microfluidic techniques and characterized using transmission electron microscopy (TEM). A sensitive and selective LC-MS/MS method was developed and validated to quantify Jaspine B concentrations in the rat plasma. The analytical method showed linearity in a wide range of concentrations with high precision. Sprague Dawley rats were used to carry out a pharmacokinetic study to assess the impact of liposomal formulation on the pharmacokinetic parameters of Jaspine B. The liposomal formulation successfully improved the PK of the drug with enhanced bioavailability, increased half-life, and circulation time in the plasma, leading to improved therapeutic outcomes.

Abstract:

Background: This study examines the challenges associated with pharmacological management in fibromyalgia (FM), a multifaceted syndrome characterized by widespread pain, cognitive impairment and fatigue. A comparative analysis of drug usage, potential drug interactions, and adherence to clinical guidelines highlights the critical need to evaluate how medications may contribute to symptoms such as fibro-fog and affect overall quality of life, with the aim of optimizing patient` well-being. Objectives: The primary aim of this study was to assess medication usage, identify potential drug interactions, and evaluate treatment suitability in FM patients, with a particular focus on recent pharmacological advancements and their impact on symptom management. Methods: This cross-sectional study analyzed medication usage and potential drug interactions in women with FM. Tools such as CheckTheMeds® and the CRIDECO Anticholinergic Load Scale were employed to assess the pharmacological appropriateness of treatments in alignment with clinical guidelines, as well as to evaluate the anticholinergic burden and its potential cognitive impacts. Results: The study included 108 women with FM, with a mean age of 54.06 ± 8.43 years. Pain management medications accounted for 72.94% of total medication prescribed. The analysis revealed a significant anticholinergic burden in 50.93% of the patients, and a total of (881 alerts were recorded for potential drug interactions). Conclusions: Pharmacological reviews are essential in the management of FM, as they enhance treatment safety, minimize risks such as CNS depression and high anticholinergic burden, and help to alleviate symptoms like fibro-fog or cognitive impairment. Personalized medication approaches can improve patient outcomes and quality of life, particularly given the complexities and lack of consensus regarding FM treatment strategies.

Abstract: Medication-related osteonecrosis of the jaw (MRONJ) is a rare adverse event associated with antiresorptive and antiangiogenic drugs that can significantly impact quality of life. In this study, we conducted a quantitative structure-activity relationship (QSAR) analysis using the U.S. Food and Drug Administration Adverse Drug Reaction Database System (FAERS) and machine learning to construct a drug prediction model for MRONJ induction based solely on chemical structure information. We analyzed 4,815 drugs from FAERS to assess their association with MRONJ and predict MRONJ-positive and MRONJ-negative drugs. By incorporating 326 chemical structure descriptors, we performed QSAR analysis on 60 positive and 108 negative drugs. Three machine learning algorithms were evaluated along with the number of chemical structure descriptors for QSAR analysis. The optimal MRONJ induction drug prediction model was established using an artificial neural network algorithm and eight chemical structure descriptors (area under the receiver operating characteristic curve = 0.778). Among these descriptors, drugs with polar surface area characteristics were identified as potentially linked to MRONJ. This study demonstrates a promising approach for predicting MRONJ risk, which could enhance drug safety assessment and streamline drug screening in clinical and preclinical settings.

Abstract: The pharmaceutical industry faces significant challenges when promising drug candi-dates fail during development due to suboptimal ADME (absorption, distribution, metab-olism, excretion) properties or toxicity concerns. Natural compounds are subject to the same pharmacokinetic considerations. In silico approaches offer a compelling advantage: they eliminate the need for physical samples and laboratory facilities, while providing rapid and cost-effective alternatives to expensive and time-consuming experimental test-ing. Computational methods can often effectively address common challenges associated with natural compounds, such as chemical instability and poor solubility. Through a re-view of the relevant scientific literature, we present a comprehensive analysis of in silico methods and tools used for ADME prediction, specifically examining their application to natural compounds. Whereas we focus on identifying the predominant computational approaches applicable to natural compounds, these tools were developed for conventional drug discovery and are of general use. We examine an array of computational approaches for evaluating natural compounds, including fundamental methods like quantum me-chanics calculations, molecular docking, and pharmacophore modeling, as well as more complex techniques such as QSAR analysis, molecular dynamics simulations, and PBPK modeling.

Abstract:

Background: Sparstolonin B (SsnB), a natural compound with an-ti-inflammatory and anti-proliferative properties, was investigated for its effects on cell viability, apoptosis, and inflammatory pathways in human colorectal cancer cells (HCT-116) and healthy human fibroblasts (BJ). Phorbol 12-myristate 13-acetate (PMA), a tumor promoter and inflammatory activator, was used to stimulate prolifer-ation and inflammatory pathways. Methods: HCT-116 and BJ cells were treated with SsnB (3.125–50 μM) or PMA (1–10 nM) for 12–18 hours. Cell viability was assessed using viability assays, while apoptosis was evaluated by cleaved caspase-3 staining, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and flow cy-tometry. Proliferation was analyzed through proliferating cell nuclear antigen (PCNA) staining. Toll-like receptor (TLR) signaling, cytokine expression, and sphingolipid lev-els were measured using immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and mass spectrometry, respectively. Results: SsnB significantly reduced HCT-116 cell viability in a dose- and time-dependent manner, with minimal effects on BJ cells. PMA stimulated proliferation, PCNA expression, and inflammatory markers, including TLR2, TLR4, MyD88, phosphorylated extracellular signal-regulated kinase (p-ERK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), and cytokines TNF-α (tumor necrosis factor-alpha), IL-1β (interleukin-1 beta), IL-6 (inter-leukin-6). SsnB suppressed PMA-induced effects and promoted apoptosis in HCT-116 cells, increasing cleaved caspase-3, TUNEL staining, and ceramide levels while de-creasing S1P (sphingosine-1-phosphate) and C1P (ceramide-1-phosphate). Conclu-sions: SsnB selectively inhibits proliferation, induces apoptosis, and modulates in-flammatory and sphingolipid pathways in colorectal cancer cells, with minimal tox-icity to healthy fibroblasts, supporting its potential as a targeted therapeutic agent.

Abstract: Clarithromycin is a commonly used macrolide antibiotic. Infection is a major source of mortality and morbidity in critical care units. Pharmacokinetics may vary during critical illness and suboptimal pharmacokinetic exposure of antimicrobials has been shown to be associated with treatment failure. The pharmacokinetics of intravenous clarithromycin in critical illness has not previously been described. Pharmacokinetic, clinical and demographic data was collected from critically unwell adults receiving intravenous clarithromycin. Drug concentrations were measured using high performance liquid chromatography/mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM version 7.5.1. Allometric weight scaling added and periods of renal replacement therapy excluded a priori. Simulations of 10,000 patients were performed to assess pharmacokinetic-pharmacodynamic (PKPD) target attainment. 121 samples were taken from 18 participants. A 2-compartment model was found to provide the best fit. The addition of covariates did not improve model fit. There was no evidence of auto-inhibition in this population. Population parameter estimates were lower than previously reported, with high interindividual variability. Simulations suggested reasonable PKPD target attainment with current dosing regimens for most organisms with known clinical breakpoints. To our knowledge, this is the first study to describe the pharmacokinetics of intravenous clarithromycin. Although our simulations suggest reasonable target attainment, further investigation into appropriate PKPD targets and clinical breakpoints for clarithromycin may enable dosing optimisation in this population.

Abstract: Elevated plasma LDL-cholesterol (LDL-C) is associated with an increased risk for atherosclerosis and development of cardiovascular disease. Elevated plasma LDL-C concentration is the result of enhanced C synthesis, C absorption and/or altered C homeostasis. Plasma LDL-C lowering can be achieved using pharmaceutical means. Statin therapy inhibits endogenous C synthesis and leads to a mean 40% LDL-C reduction. Ezetimibe inhibits C absorption and achieves an average 20% LDL-C reduction with a 10 mg daily intake. Phytosterol therapy is established by food supplements enriched in phytosterols and/or phytostanols. A dosage of 2 to 3 grams a day reduces C absorption and leads to an average 10% LDL-C reduction. This dosage expresses a 10-fold increased daily intake for phytosterols or a 100-fold increased intake of phytostanols. Phytosterol and -stanol enriched food supplements are freely available in the supermarket. The majority of consumers may be healthy subjects with a plasma LDL-C in the normal range. Scientific evidence reveals that increased phytosterol intake may be associated with development of atherosclerosis. The degree of increased risk is dependent on the patient’s genetic polymorphisms in NPC1L1 and ABCG5/G8 transport proteins as well as on the established risk reduction due to LDL-C lowering. Subjects with a normal or only slightly elevated LDL-C have only minimal LDL-C lowering and lack the compensation for the potential increased risk for atherosclerosis by phytosterols. Based on the potential risk induction, the availability of phytosterol fortified food supplements must be abandoned from the supermarket.