Search Results (174)

Despite major advances in guideline-directed cardiovascular therapy, residual cardiovascular risk persists, partly driven by oxidative stress, chronic inflammation, endothelial dysfunction, and mitochondrial injury not fully addressed by current drugs. Translation of plant-based cardioprotectants is constrained by preparation-dependent variability in extract chemistry (plant part/cultivar/processing and extraction method), low and variable systemic exposure for key actives (notably curcuminoids and many polyphenols), and clinically relevant safety/interaction considerations (e.g., hepatotoxicity reports with concentrated green tea extracts and antiplatelet-related bleeding-risk considerations for some botanicals). We therefore provide a mechanism- and translation-oriented synthesis of evidence for cardioprotective botanicals, chosen for long-standing traditional use and scientific validation with reproducible experimental data and, where available, human studies, including Crataegus monogyna, Allium sativum, Olea europaea, Ginkgo biloba, Leonurus cardiaca, and Melissa officinalis. Across studies, polyphenols (especially flavonoids and phenolic acids) and organosulfur compounds are most consistently associated with cardioprotection, while terpene-derived constituents and secoiridoids contribute mechanistically in plant-specific settings (e.g., Ginkgo and Olea). Predominantly in experimental models, these agents engage redox-adaptive (Nrf2), mitochondrial (mPTP), endothelial, and inflammatory (NF-κB) pathways, with reported reductions in ischemia–reperfusion injury, oxidative damage, and apoptosis. Clinical evidence remains heterogeneous and is largely confined to short-term studies and surrogate outcomes (blood pressure, lipids, oxidative biomarkers, endothelial function), with scarce data on hard cardiovascular endpoints or event reduction. Priorities include standardized, chemotype-controlled formulations with PK/PD-guided dosing and adequately powered randomized trials that assess safety and herb–drug interactions. Full article

Workers’ exposure to silica dust is a global occupational and public health concern and is particularly prevalent in Southern Africa, mainly because of inadequate dust control measures. It is worsened by the high prevalence of HIV/AIDS, which exacerbates tuberculosis and other occupational lung diseases. The prevalence of silicosis in the region ranges from 9 to 51%; however, silica dust exposure levels and controls, especially in the informal mining sector, particularly in artisanal small-scale mines (ASMs), leave much to be desired. This is important because silicosis is incurable and can only be eliminated by preventing worker exposure. Additionally, several studies have indicated inadequate occupational health and safety policies, weak inspection systems, inadequate monitoring and control technologies, and inadequate occupational health and hygiene skills. Furthermore, there is a near-absence of silica dust analysis laboratories in southern Africa, except in South Africa. This protocol aims to systematically evaluate the effectiveness of respirable dust and respirable crystalline silica dust exposure evaluation and control methodology for the mining industry. The study will entail testing the effectiveness of current dust control measures for controlling microscale particles using various exposure dose metrics, such as mass, number, and lung surface area concentrations. This will be achieved using a portable Fourier transform infrared spectroscope (FTIR) (Nanozen Industries Inc., Burnaby, BC, Canada), the Nanozen DustCount, which measures both the mass and particle size distribution. The surface area concentration will be analysed by inputting the particle size distribution (PSD) results into the Multiple-Path Particle Dosimetry Model (MPPD) to estimate the retained and cleared doses. The MPPD will help us understand the sub-micron dust deposition and the reduction rate using the controls. To the best of our knowledge, the proposed approach has never been used elsewhere or in our settings. The proposed approach will reduce dependence on highly skilled individuals, reduce the turnaround sampling and analysis time, and provide a reference for regional harmonised occupational exposure limit (OEL) guidelines as a guiding document on how to meet occupational health, safety and environment (OHSE) requirements in ASM settings. Therefore, the outcome of this study will influence policy reforms and protect hundreds of thousands of employees currently working without any form of exposure prevention or protection. Full article

Background: Teicoplanin is widely used for the empirical and targeted treatment of febrile neutropenia in patients with hematological malignancies. However, the pathophysiological alterations typical of this population may substantially affect drug exposure. The aim of this study was to develop and validate a population pharmacokinetic (PopPK) model of teicoplanin in adult hematological patients and to propose individualized dosing strategies. Methods: A retrospective, single-center study including 151 patients and 263 serum concentrations was conducted, with participants assigned to development (n = 100) and validation (n = 51) cohorts. Concentrations were quantified using a turbidimetric immunoassay, and the PopPK model was developed in NONMEM using FOCE-I. Results: Teicoplanin pharmacokinetics were described by a one-compartment model with first-order elimination. Ideal body weight, estimated glomerular filtration rate, and age were identified as significant predictors of clearance. Internal and external validation confirmed the robustness and predictive performance of the model. Monte Carlo simulations showed that conventional regimens (6 mg/kg every 12 h for three loading doses, followed by 6 mg/kg once-daily, or 600 mg every 12 h for three loading doses, followed by 600 mg once-daily) are insufficient to achieve therapeutic trough concentrations (≥15–20 mg/L) within the first 72 h, particularly in patients with preserved renal function or higher body weight. An intensified regimen consisting of five loading doses of 12 mg/kg every 12 h, followed by 12 mg/kg once-daily, enabled rapid attainment and maintenance of trough concentrations ≥ 20 mg/L in patients with lower to intermediate ideal body weight. Conclusions: These findings underscore the importance of intensified dosing strategies and covariate-guided individualization supported by therapeutic drug monitoring to achieve optimal teicoplanin exposure in this vulnerable patient group. Full article

Industrial air emissions are major contributors to human exposure to toxic pollutants, posing significant health risks. Life cycle assessment (LCA) is increasingly used to quantify human toxicity impacts from industrial processes. Conventional LCA often overlooks spatial and temporal variability, limiting its ability to capture actual inhaled doses and exposure-driven impacts. To address this, we developed a site-dependent dynamic LCA (SdDLCA) framework that integrates conventional LCA with Enhanced Structural Path Analysis (ESPA) and atmospheric dispersion modeling. Applied to the production of double-glazed PVC windows for a residential project, the framework generates high-resolution, site-specific emission inventories for three key pollutants: nitrogen oxides (NO_x), sulfur dioxide (SO₂), and fine particulate matter (PM_2.5). Local concentration fields are compared with World Health Organization (WHO) air quality thresholds to identify hotspots and periods of elevated exposure. By coupling these fields with the ReCiPe 2016 endpoint methodology and localized demographic and meteorological data, SdDLCA quantifies human health impacts in Disability-Adjusted Life Years (DALYs), providing a direct measure of inhalation toxicity. This approach enhances LCA’s ability to capture exposure-driven effects, identifies populations at greatest risk, and offers a robust, evidence-based tool to guide industrial planning and operations that minimize health hazards from air emissions. Full article

Background/Objective: Early hemodynamic instability in sepsis arises from endothelial dysfunction and vasoplegia before capillary leakage and organ failure occur. Albumin administration guided by serum concentration or shock criteria has not improved outcomes. This review synthesized evidence supporting an early, physiology-guided framework for albumin and norepinephrine use in pre-δ vasoplegic sepsis. Methods: A narrative synthesis of experimental and clinical studies examined endothelial injury, sepsis phenotypes, hemodynamic monitoring, biochemical markers, and intravascular albumin mass. Evidence from phenotype cohorts was integrated to construct a physiology-based therapeutic framework. Results: The δ phenotype consistently emerged as a vasoplegic, hyperinflammatory endotype with hypoalbuminemia, elevated lactate, and the highest mortality. Studies showed 20–25% of patients with community-acquired sepsis exhibit early vasoplegia, with low systemic vascular resistance and high cardiac output. Mass-balance analyses showed intravascular albumin mass declines early in sepsis, correlate inversely with fluid balance, and predict mortality. These findings suggest early low-dose norepinephrine may stabilize perfusion pressure, while albumin use should follow intravascular albumin mass trajectories. A dynamic exclusion concept proposes withholding albumin during capillary leak and reintroducing it when intravascular albumin mass stabilizes. Conclusions: Albumin therapy in sepsis should shift from late concentration-based to early physiology-guided endothelial protection. Monitoring intravascular albumin mass, lactate, and fluid balance may guide targeted norepinephrine and albumin use before δ-type endothelial failure occurs. This framework needs phenotype-stratified validation. Full article

Volcanic eruptions can mobilize naturally occurring toxic elements such as arsenic into surrounding ecosystems, contaminating soil, water, and food webs. Despite increasing evidence of arsenic enrichment in volcanic regions, comprehensive exposure assessments that integrate dietary and drinking water pathways remain limited, particularly in post-eruption contexts where baseline data are scarce. Following the 2020 Taal Volcano eruption, this study conducted a probabilistic risk assessment to quantify aggregate exposure to inorganic arsenic (iAs) among residents of Batangas, Philippines. A Monte Carlo simulation framework (10,000 iterations) integrated post-eruption environmental data on total arsenic in soil, lake water, drinking water and clam tissues with modeled bioaccumulation and transfer factors for fish and major terrestrial crops. Two exposure scenarios, lower bound (50% iAs fraction) and upper bound (90% iAs fraction), were applied to capture uncertainty in arsenic speciation and bioavailability. Simulated iAs concentrations followed the order rice > corn > vegetables > root crops. Aggregate daily iAs doses averaged 3.0 ± 1.4 µg/kg bw/day (lower bound) and 4.0 ± 2.0 µg/kg bw/day (upper bound), with females showing slightly higher exposures and pregnant women exhibiting lower doses. Sensitivity analysis identified clam intake, rice intake, and iAs in rice, clams, and drinking water as dominant determinants of total exposure. All simulated individuals exceeded the U.S. EPA non-cancer reference dose (HQ > 1) and cancer risk benchmark (10⁻⁶–10⁻⁴), indicating substantial health concern. These findings highlight the urgent need for sustained environmental monitoring, arsenic speciation analyses, biomonitoring, and public health programs to guide evidence-based management in arsenic-affected volcanic regions. Full article

This study aimed to evaluate the response mechanisms of zebrafish larvae to Norfloxacin nicotinate (NOR-N) exposure. Embryos were exposed to NOR-N from 4 h post-fertilization (hpf) until 96 hpf. The exposure concentrations included 0.002, 0.2, 1, and 5 mg/L (simulating both normal and exceptionally high environmentally relevant levels of NOR), as well as a high dose of 25 mg/L. Subsequent analyses focused on apoptosis, neurodevelopment, and DNA methylation in the resulting zebrafish larvae. The results showed that high-dose NOR-N (≥5 mg/L) induced obvious apoptotic cell death in zebrafish larvae, accompanied by increased activities of Cas3 and Cas9, up-regulated P53, Bax, Puma, Apaf1, Cas3 and Cas9 genes expression, and reduced Mdm2 levels and Bcl2/Bax ratio. Moreover, exposure to 5 and/or 25 mg/L NOR-N resulted in a significant up-regulation of neurodevelopment-related genes (Sox2, Sox3 and Sox19a), concomitantly with a marked decline in the transcription of DNA methylation genes, including Dnmt1, Dnmt3a1, Dnmt3b1, Dnmt3b2 and Dnmt3b4. Overall, our findings demonstrated that NOR-N exposure could induce apoptosis, developmental neurotoxicity and aberrant DNA methylation in zebrafish larvae. These findings provide insights to guide the safe application of NOR-N in aquaculture and support the assessment of its potential ecological risks to aquatic ecosystems. Full article

Background: The role of digoxin in atrial fibrillation, particularly in patients with heart failure, has long been debated. Observational studies reporting higher mortality have fueled skepticism, yet growing evidence suggests that these findings largely reflect prescription bias, confounding by indication, and inadequate adjustment for serum-level rather than intrinsic toxicity. Objective: To reassess digoxin’s role in atrial fibrillation with heart failure using contemporary evidence and to propose a physiology-based, personalized monitoring framework. Evidence review: We reevaluated the studies that initially linked digoxin to excess mortality and reassessed these associations through three analytic pillars: randomized evidence, bias deconstruction, and exposure–response relationships. Across datasets, low serum digoxin concentrations were consistently associated with stable resting rate control without increasing mortality. Key findings: Low-dose, continuously administered digoxin is a viable second-line option for atrial fibrillation rate control in patients who are hypotensive or intolerant of β-blockers. Safety is concentration-dependent; adverse outcomes increase at higher serum digoxin concentration (≥1.2 ng/mL). Resting heart rate can serve as a contextual surrogate of exposure: persistent HR > 100 bpm in stable patients usually reflects underexposure rather than digoxin toxicity, whereas bradycardia should prompt immediate serum digoxin concentration testing. Proposal: A probability-based monitoring model that integrates heart rate, renal function, dosage, electrolytes, and drug–drug interactions to guide when serum digoxin concentration measurement is warranted. As a future direction, a supervised “pill-in-the-pocket” supplemental dose strategy could be evaluated for transient tachycardia in selected, stable patients. Conclusions: When properly dosed and contextually monitored, digoxin remains a safe, effective, and individualized rate-control option in atrial fibrillation with heart failure. Prospective validation of probability-guided monitoring and evaluation of a “pill-in-the-pocket” approach could simplify digoxin management while maintaining safety. Full article

Senna petersiana (Bolle) Lock is a chemically diverse plant widely recognized for its ethnomedicinal applications across various traditional medical systems. It is native to and widely distributed in African countries, including Ethiopia, Cameroon, and South Africa. This review integrates the phytochemical composition, biological activities, and toxicological effects of S. petersiana. Phytochemical analyses reveal the presence of numerous classes of compounds, including alkaloids, flavonoids, phenolics, anthraquinones, chromones, and sterol glycosides, with variations in concentration across different plant parts. Quantitative studies highlight particularly high levels of phenolics and flavonoids in ethanol, methanol, and acetone extracts, correlating these with enhanced biological activities. Pharmacological investigations demonstrate a spectrum of activities, including antibacterial, antioxidant, anti-inflammatory, antiviral, anthelmintic, and anticancer effects, supporting many of the plant’s traditional uses. Toxicological assessments suggest relative safety at moderate doses, though further evaluation is necessary for specific cell types and high-dose exposures. Despite the promising bioactivities, the mechanisms of action and in vivo efficacy of isolated compounds remain underexplored. Future research should focus on bioassay-guided isolation, detailed pharmacodynamic studies, and comprehensive toxicological profiling to validate and harness the therapeutic potential of S. petersiana. This review highlights the plant’s biochemical complexity and paves the way for its development as a valuable phytopharmaceutical agent. Full article

Redox imbalance and epigenetic dysregulation, which both contribute to tumor initiation, survival, and resistance to therapy, are intimately linked to the progression of cancer. Reactive oxygen species (ROS) have two contrasting effects: at moderate concentrations, they promote angiogenesis and oncogenic signaling, whereas at high concentrations, they trigger apoptosis. Oxidative stress alters histone modifications, DNA methylation, and non-coding RNA (ncRNA) expression, reshaping the epigenetic landscape and supporting malignant phenotypes. Plant-derived antioxidants, including flavonoids, polyphenols, alkaloids, and terpenoids, act as dual modulators of cancer biology. They scavenge or regulate reactive oxygen species (ROS), restore redox balance, activate tumor suppressor pathways, inhibit oncogenic mechanisms, and reverse abnormal epigenetic marks. Compounds such as resveratrol, curcumin, epigallocatechin gallate (EGCG), quercetin, and sulforaphane modulate DNA methyltransferases (DNMTs), histone deacetylases (HDACs), and non-coding RNA networks, and can enhance chemotherapy and radiation therapy. Despite promising mechanisms, challenges remain in translational efficacy, optimal dosing, and bioavailability. This review emphasizes the potential of plant-derived antioxidants as precision oncology adjuncts and highlights the need for biomarker-guided strategies, nano-delivery systems, and clinical validation to fully realize their therapeutic benefits. Plant-derived antioxidants mitigate ROS-induced oncogenic signaling, as evidenced by in vitro and clinical models. Full article

Background: Meropenem (MEM) is frequently prescribed for the empirical management of severe infections in the pediatric intensive care unit (PICU). Critically ill children exhibit substantial pharmacokinetic (PK) variability, and current dosing strategies remain inadequately evaluated, particularly in neonates, infants, and those with altered renal function. Methods: This study employed a dual modeling approach integrating population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) methodologies. Clinical data from two PICUs were utilized for PopPK model development and PBPK model evaluation. Both models were rigorously assessed using goodness-of-fit plots and prediction-based metrics. Monte Carlo simulations were subsequently conducted to calculate the probability of target attainment (PTA) for multiple dosing regimens across MICs of 0.25–16 mg/L. The pharmacodynamic target (PDT) was defined as maintaining unbound plasma concentrations above the MIC for 100% of the dosing interval (100% ƒT _{> MIC}), and dosing regimens were considered acceptable if the PTA exceeded 90% for efficacy while avoiding potential toxicity (Css ≥ 50 mg/L). Results: A total of 202 MEM plasma concentrations from 101 pediatric patients were analyzed. Marked inter-individual variability in MEM pharmacokinetics and pharmacodynamics was observed. Augmented renal clearance (ARC) was frequently identified in PICU patients. We simultaneously developed a two-compartment population pharmacokinetic model incorporating body weight and estimated glomerular filtration rate, and a whole-body physiologically based pharmacokinetic model scaled from adults with adjustments for transporter ontogeny and renal function. The PopPK model, by incorporating interindividual variability on clearance and volume of distribution, captured a wider range of drug exposures and demonstrated superior predictive performance, particularly in subgroups with high eGFR. The PBPK model showed higher precision in the low eGFR subgroup but slightly lower overall predictive accuracy. Both models identified ARC as a key driver of subtherapeutic exposure. Standard regimens were insufficient for preterm neonates when the MIC was ≥4 mg/L, and even the maximum label-recommended dose failed to achieve the pharmacodynamic target for infants older than 1 month when the MIC was ≥2 mg/L. Conclusions: Both PBPK and PopPK frameworks reliably predicted MEM pharmacokinetics in critically ill pediatric patients, with complementary strengths across renal function strata. Model-informed simulations highlighted the inadequacy of standard dosing under conditions of ARC or elevated MIC, supporting individualized, precision-guided dosing strategies based on age, eGFR, and pathogen MIC. Full article

Background/Objectives: The goal is to provide a straightforward framework for generating SRS-SRT plans that reliably meet high-quality dosimetric standards. That posed some questions such as which plan quality metrics should be utilized to evaluate a plan, what influences plan quality metrics the most, and finally, how to best optimize plan geometry. Our work has primarily concentrated on the second question, guided by our clinical experience. Methods: A dataset for statistical analysis was compiled by retrospectively reviewing 200 individual SRS-SRT target volumes from two centers. From the gathered data, several Linear Regression models were generated to assess the variability of plan quality metrics using statistical analysis. The most important regressor in the models were revealed to be target volume (TV), followed by a flag type variable that indicates whether the plan used to treat the referenced target contained multiple targets (MT) or not. Results: Every doubling of TV lowers Gradient Index (GI) sharply (−0.55 to −0.17) while Gradient Measure (GM) increases moderately (+0.024 cm to +0.07 cm). The model explains 85% of the variation in GI (R² = 0.85) and 84% of GM. Conclusions: In small lesions, GI seems to be a more sensitive evaluation metric for sub-CC SRS targets, compared to GM. Dose per fraction appeared to have had no significant effect. Treating multiple targets in the same plan appears to add an average of +0.19 to GI, independent of volume, while for GM by +0.027 cm. Full article

Background: Commercial oral care products commonly incorporate synthetic antimicrobials such as cetylpyridinium chloride (Cetyl Cl.), L-Arginine (L-arg.), and stannous fluoride (SnF₂). Although effective against oral pathogens, these agents are often associated with adverse effects including mucosal irritation, taste alteration, and disruption of the oral microbiome. These limitations have spurred growing interest in safer, plant-based alternatives. In this study, we present a two-pronged in vitro oral care testing model that integrates cell assays with machine-guided quantitative microscopy analyses to assess both antibacterial efficacy and host biocompatibility of botanical extracts. Methods: Using Miswak (Salvadora persica) and Neem (Azadirachta indica) as representative natural products, we conducted antibacterial and antibiofilm testing including the evaluation of the minimum inhibitory concentration (MIC), minimum biofilm inhibitory concentration (MBIC), and minimum biofilm eradication concentration (MBEC), alongside biocompatibility assessments via MTT cell viability assays on probiotic bacteria and mammalian oral cells. To evaluate biofilm structure and disruption, we employed scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM), augmented with machine-guided Weka segmentation and automated image analysis. Results: Our findings show that Miswak and Neem extracts exhibited 75–100% antibacterial and antibiofilm efficacy against all tested bacteria, as demonstrated by cell assays and microscopy analyses, comparable to synthetic oral care agents. They also maintained ~100% viability toward commensal microbes and mammalian oral cells, whereas Cetyl Cl. and SnF₂ showed dose-dependent cytotoxicity. Conclusions: This dual-assessment oral care testing model provides a comprehensive and biologically relevant framework for the discovery and screening of safe and effective natural herbal extracts in oral care applications. Full article

The widespread use of pharmaceutical agents highlights the importance of identifying potential pharmacological interactions with epinephrine, the most frequently used vasoconstrictor in dental practice. Dentists must be aware of possible risks in order to adjust anesthetic protocols, when necessary. The principal aim is to prevent complications and ensure patient safety. This review analyzes clinical data from the international literature on pharmacological interactions involving low-dose epinephrine, corresponding to the doses typically used in dental procedures. These interactions are subsequently classified according to their severity and documentation level, based on the criteria of the UpToDate Lexidrug platform. In addition, management strategies are proposed to guide dental practitioners in clinical decision-making. A literature search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library databases, using specific keywords. In total, 24 studies met the inclusion criteria, with the earliest published in 1968 and the most recent in 2022. Nine pharmacological categories were identified and presented in tables. The dosage of epinephrine plays a key role in the likelihood of pharmacological interactions, which appear to be less frequent at low concentrations typically used in dentistry. However, patient-specific factors, such as overall health status, should also be carefully considered during clinical assessment. Full article

Background: Heart failure (HF), as the end stage of various cardiac diseases, alters blood flow to key organs responsible for drug clearance. This can lead to unpredictable and often suboptimal drug exposure, creating a critical need for quantitative tools to guide precise dosing in this vulnerable population. Methods: This study aimed to establish a whole-body physiologically based pharmacokinetic (PBPK) model for characterizing drug pharmacokinetics in both healthy subjects and patients across the HF severity spectrum. Eight commonly used drugs (digoxin, furosemide, bumetanide, torasemide, captopril, valsartan, felodipine and midazolam) for treating HF and its comorbidities were selected. Following successful validation against clinical data from healthy subjects, the PBPK model was extrapolated to HF patients. Pharmacokinetics of the eight drugs in 1000 virtual HF patients were simulated by replacing tissue blood flows and compared using clinical observations. Results: Most of the observed concentrations were encompassed within the 5th–95th percentiles of simulated values from 1000 virtual HF patients. Predicted area under the concentration–time curve and maximum plasma concentration fell within the 0.5~2.0-fold range relative to clinical observations. Sensitivity analysis demonstrated that intrinsic renal clearance, unbound fraction in blood, muscular blood flow, and effective permeability coefficient significantly impact plasma exposure of digoxin at a steady state. Oral digoxin dosing regimens for HF patients were optimized via the validated PBPK model to ensure that steady-state plasma concentrations in all HF patients remain below the toxicity threshold (2.0 ng/mL). Conclusions: A PBPK model was successfully developed to predict the plasma concentration–time profiles of the eight tested drugs in both healthy subjects and HF patients. Furthermore, this model may also be applied to guide digoxin dose optimization for HF patients. Full article