Volume Of Distribution Research Articles

Brain inflammation co-localizes highly with tau in mild cognitive impairment due to early-onset Alzheimer's disease.

Brain inflammation, with an increased density of microglia and macrophages, is an important component of Alzheimer's disease (AD) and a potential therapeutic target. However, it is incompletely characterized, particularly in patients whose disease begins before the age of 65 years and, thus, have few co-pathologies. Inflammation has been usefully imaged with translocator protein (TSPO) positron emission tomography (PET), but most inflammation PET tracers cannot image subjects with a low-binder TSPO rs6971 genotype. In an important development, participants with any TSPO genotype can be imaged with a novel tracer, [11C]ER176, that has a high binding potential and a more favorable metabolite profile than other TSPO tracers currently available. We applied [11C]ER176 to detect brain inflammation in mild cognitive impairment (MCI) caused by early-onset AD. Furthermore, we sought to correlate the brain localization of inflammation, volume loss, elevated Aβ and tau. We studied brain inflammation in 25 patients with early-onset amnestic MCI (average age 59 ± 4.5 years, 10 women) and 23 healthy controls (average age 65 ± 6.0 years, 12 women), both groups with a similar proportion of all three TSPO-binding affinities. [11C]ER176 total distribution volume (VT), obtained with an arterial input function, was compared across patients and controls using voxel-wise and region-wise analyses. In addition to inflammation PET, most MCI patients had Aβ (n=23), and tau PET (n=21). For Aβ and tau tracers, standard uptake value ratios (SUVRs) were calculated using cerebellar grey matter as region of reference. Regional correlations among the three tracers were determined. Data were corrected for partial volume effect. Cognitive performance was studied with standard neuropsychological tools. In MCI caused by early-onset AD, there was inflammation in the default network, reaching statistical significance in precuneus and lateral temporal and parietal association cortex bilaterally, and in the right amygdala. Topographically, inflammation co-localized most strongly with tau (r= 0.63 ± 0.24). This correlation was higher than the co-localization of Aβ with tau (r= 0.55±0.25) and of inflammation with Aβ (0.43±0.22). Inflammation co-localized least with atrophy (-0.29±0.26). These regional correlations could be detected in participants with any of the three rs6971 TSPO polymorphisms. Inflammation in AD-related regions correlated with impaired cognitive scores. Our data highlight the importance of inflammation, a potential therapeutic target, in the AD process. Furthermore, they support the notion that, as shown in experimental tissue and animal models, the propagation of tau in humans is associated with brain inflammation.

Double emulsion generation in shear-thinning fluids under electric field effects

Double emulsions are encapsulated microstructures with medical, food, and cosmetics applications. Precise control over their parameters, such as volume, thickness, and size distribution, is crucial. This study numerically investigates, for the first time, the generation of double emulsions in a shear-thinning outer fluid under the influence of an external DC electric field. A dual co-flowing microfluidic device is chosen as the flow domain, and the shear-thinning behavior of the outer fluid is approximated by the Carreau–Yasuda rheological model. The governing equations are discretized on structured numerical grids using the VOF-CSF model and the finite volume method. The combined effects of the shear-thinning behavior and electric forces on compound droplet formation parameters, including volume, eccentricity, maximum thickness, and jet length, are studied carefully. Results show that for highly shear-thinning fluids, the application of electric forces can ensure the generation of desired compound droplets, which is not feasible without electric field effects. However, excessive electric forces can disrupt the droplet generation process, especially for moderate to low shear-thinning fluids. These findings provide new insights into the role of external electric fields in double emulsion generation and highlight their potential to optimize the production process.

Extracorporeal treatment in poisoning

In rare cases, intoxicated patients may require an extracorporeal procedure for enhanced toxin elimination. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup provides consensus- and evidence-based recommendations regarding the use of extracorporeal procedures in the management of critically ill, poisoned patients, with ongoing updates. Extracorporeal clearance is highest for low molecular weight substances with low volume of distribution, low plasma protein binding, and high water-solubility. To maximize the effect of extracorporeal clearance, blood and dialysate flow rates should be as high as possible, and the membrane with the largest surface area should be utilized. Intermittent hemodialysis is the most commonly employed extracorporeal procedure due to its highest effectiveness, while hemodynamically compromised patients can benefit from acontinuous procedure.

On the measurement of the aerodynamic features of composite structures under subsonic airflow using mathematical modeling and machine learning method

This study investigates the aerodynamic features of functionally graded triply periodic minimal surface (FG-TPMS) structures under subsonic airflow using a combination of mathematical modeling and machine learning methods. The modified supersonic piston theory of Krumhaar is used to quantify the aerodynamic stiffness and damping matrices. Using characteristics and six distinct patterns of volume distribution of FG-TPMS materials in terms of their mechanical qualities, Hamilton’s principle, and parabolic shear deformation theory are used to extract the governing equations of the presented composite structure. After that, the differential quadrature method at the discrete places and Lagrange interpolated polynomials and Kronecker product are used to solve the governing equations in the numerical domain. This study highlights the potential of integrating advanced computational techniques with machine learning to address complex engineering problems. The findings provide valuable insights into the aerodynamic optimization of sandwich structures, paving the way for their more efficient and effective design in aerospace engineering. As an important outcome for related industries, the displacement field along with the Z direction increases by increasing the angle of airflow by approximately 9 % while this value for the X, and Y directions are 7 %, and 6 %, respectively. The proposed methodology offers a powerful tool for engineers and researchers seeking to optimize the performance of advanced composite materials under subsonic airflow conditions.

Enhancing spatial modeling and risk mapping of six air pollutants using synthetic data integration with convolutional neural networks

Air pollution poses significant risks to human health and the environment, necessitating effective air quality management strategies. This study presents a novel approach to air quality management by integrating an autoencoder (AE) with a convolutional neural network (CNN) algorithm in Tehran city of Iran. One of the primary and vital problems in deep learning is model complexity, and the complexity of a model is affected by data distribution, data complexity, and information volume. AE provide a helpful way to denoise input data and make building deep learning models much more efficient. The proposed methodology enables spatial modeling and risk mapping of six air pollutants, namely, particulate matter 2.5 (PM2.5), particulate matter 10 (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), and carbon monoxide (CO). For air pollution modelling, data from a spatial database containing the annual average of six pollutants from 2012 to 2022 was utilized. The model considered various parameters influencing air pollution: altitude, humidity, distance to industrial areas, NDVI (normalized difference vegetation index), population density, rainfall, distance to the street, temperature, traffic volume, wind direction, and wind speed. The risk map accuracy was assessed using the area under the receiver operating characteristic (ROC) curve for six pollutants. Among them, NO2, PM10, CO, PM2.5, O3, and SO2 exhibited the highest accuracy with values of 0.964, 0.95, 0.896, 0.878, 0.877, and 0.811, respectively, in the risk map generated by the CNN-AE model. The findings demonstrated the CNN-AE model’s impressive precision when generating the pollution risk map.

Silicon Optrode with a Micromirror‐Tip Providing Tunable Beam Profile During Infrared Neuromodulation of the Rat Neocortex

AbstractInfrared (IR) neuromodulation holds an increasing potential in brain research, which is fueled by novel neuroengineering approaches facilitating the exploration of the biophysical mechanism in the microscale. The group lays down the fundamentals of spatially controlled optical manipulation of inherently temperature‐sensitive neuronal populations. The concept and in vivo validation of a multifunctional, optical stimulation microdevice is presented, which expands the capabilities of conventional optrodes by coupling IR light through a monolithically integrated parabolic micromirror. Heat distribution in the irradiated volume is experimentally analyzed, and the performance of the integrated electrophysiological recording components of the device is tested in the neocortex of anesthetized rodents. Evoked single‐cell responses upon IR irradiation through the novel microtool are evaluated in multiple trials. The safe operation of the implanted device is also presented using immunohistological methods. The results confirm that shift in temperature distribution in the vicinity of the optrode tip can be controlled by the integrated photonic components, and in parallel with the optical stimulation, the device is suitable to interrogate the evoked electrophysiological activity at the single neuron level. The customizable and scalable optrode system provides a new pathway to tailor the location of the heat maximum during infrared neural stimulation.

Subsurface Profiling of Ion Migration and Swelling in Conducting Polymer Actuators with Modulated Electrochemical Atomic Force Microscopy.

Understanding the dynamics of ion migration and volume change is crucial to studying the functionality and long-term stability of soft polymeric materials operating at liquid interfaces, but the subsurface characterization of swelling processes in these systems remains elusive. In this work, we address the issue using modulated electrochemical atomic force microscopy as a depth-sensitive technique to study electroswelling effects in the high-performance actuator material polypyrrole doped with dodecylbenzenesulfonate (Ppy:DBS). We perform multidimensional measurements combining local electroswelling and electrochemical impedance spectroscopies on microstructured Ppy:DBS actuators. We interpret charge accumulation in the polymeric matrix with a quantitative model, giving access to both the spatiotemporal dynamics of ion migration and the distribution of electroswelling in the electroactive polymer layer. The findings demonstrate a nonuniform distribution of the effective ionic volume in the Ppy:DBS layer depending on the film morphology and redox state. Our findings indicate that the highly efficient actuation performance of Ppy:DBS is caused by rearrangements of the polymer microstructure induced by charge accumulation in the soft polymeric matrix, increasing the effective ionic volume in the bulk of the electroactive film for up to two times the value measured in free water.

Crack Initiation in Compacted Graphite Iron with Random Microstructure: Effect of Volume Fraction and Distribution of Particles.

Thanks to the distinctive morphology of graphite particles in its microstructure, compacted graphite iron (CGI) exhibits excellent thermal conductivity together with high strength and durability. CGI is extensively used in many applications, e.g., engine cylinder heads and brakes. The structural integrity of such metal-matrix materials is controlled by the generation and growth of microcracks. Although the effects of the volume fraction and morphology of graphite inclusions on the tensile response of CGI were investigated in recent years, their influence on crack initiation is still unknown. Experimental studies of crack initiation require a considerable amount of time and resources due to the highly complicated geometries of graphite inclusions scattered throughout the metallic matrix. Therefore, developing a 2D computational framework for CGI with a random microstructure capable of predicting the crack initiation and path is desirable. In this work, an integrated numerical model is developed for the analysis of the effects of volume fraction and nodularity on the mechanical properties of CGI as well as its damage and failure behaviours. Finite-element models of random microstructure are generated using an in-house Python script. The determination of spacings between a graphite inclusion and its four adjacent particles is performed with a plugin, written in Java and implemented in ImageJ. To analyse the orientation effect of inclusions, a statistical analysis is implemented for representative elements in this research. Further, Johnson-Cook damage criteria are used to predict crack initiation in the developed models. The numerical simulations are validated with conventional tensile-test data. The created models can support the understanding of the fracture behaviour of CGI under mechanical load, and the proposed approach can be utilised to design metal-matrix composites with optimised mechanical properties and performance.

Evaluation of the pharmacokinetics, chylomicron inhibition, and toxicity of colchicine in rats given low doses

Colchicine (COL) is known for its ability to inhibit the formation of intestinal chylomicrons and has been utilized as a non-surgical tool to explore drug absorption via the intestinal lymphatics. However, there is limited understanding of its pharmacokinetics and its relationship to effect and toxicity with the doses used. This study aimed to provide comprehensive COL pharmacokinetic data and correlate it with the lymphatic-blocking and toxicological effects of low-doses. Male Sprague-Dawley rats with jugular-vein cannulation (JVC) received 0.1 to 0.5 mg/kg COL via oral, 0.25 mg/kg intraperitoneal, and 0.1 mg/kg intravenous routes, followed by blood and urine sampling for LC-MS/MS analysis. Effects on lipid absorption were assessed in another eight JVC rats receiving peanut oil with and without COL, followed by blood pharmacokinetic and plasma biochemistry analysis. The results revealed that COL exhibited moderate extraction ratio and high volume of distribution, with low oral bioavailability (<8%). About 20 % was recovered in the urine after parenteral dosing. Modest but significant reductions in cholesterol absorption was observed after oral doses of 0.5 mg/kg, accompanied by signs of inflammation and increased liver enzymes persisting for a week. The effect of COL on triglycerides formation was not significant. Despite its use as a non-surgical tool in rats to investigate drug absorption via the lymphatic pathway, COL demonstrated increased levels of liver function enzymes, emphasizing the need for caution and dose optimization in its utilization.

Clinical value identification of RDW on in-hospital death in unruptured abdominal aortic aneurysm.

This study aimed to identify highly valuable blood indicators for predicting the clinical outcomes of patients with aortic aneurysms (AA). Baseline data of 1180 patients and 16 blood indicators were obtained from the public Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. The association of blood indicators with 4 types of clinical outcomes was analyzed, and the prediction performance of core indicators on different outcomes was next evaluated. Then, we explored the detailed association between core indicators and key outcomes among subgroups. Finally, a machine learning model was established to improve the prediction performance. Generalized linear regression analysis indicated that only red cell volume distribution width (RDW) was commonly associated with 4 end-points including surgery requirement, ICU stay requirement, length of hospital stay, and in-hospital death (all P < .05). Further, RDW showed the best performance for predicting in-hospital death by receiver operating characteristic (ROC) analysis. The significant association between RDW and in-hospital death was then determined by 3 logistic regression models adjusting for different variables (all P < .05). Stratification analysis showed that their association was mainly observed in unruptured AA and abdominal AA (AAA, all P < .05). We subsequently established an RDW-based model for predicting the in-hospital death only in patients with unruptured AAA. The favorable prediction performance of the RDW-based model was verified in training, validation, and test sets. RDW was found to make the greatest contribution to in-hospital death within the model. RDW had favorable clinical value for predicting the in-hospital death of patients, especially in unruptured AAA.

Toxicokinetics of α- and β-amanitin in mice following single and combined administrations: Simulating in vivo amatoxins processes in clinical cases

α-Amanitin and β-amanitin, two of the most toxic amatoxin compounds, typically coexist in the majority of Amanita mushrooms. The aim of this study was to use a newly developed ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method to determine the toxicokinetics and tissue distribution of α- and β-amanitin following single or combined oral (po) administration in mice. α-Amanitin and β-amanitin administered at 2 or 10 mg/kg doses showed similar toxicokinetic profiles, except for peak concentration (Cmax). The elimination half-life (t1/2) values of α-amanitin and β-amanitin in mice were 2.4–2.8 h and 2.5−2.7 h, respectively. Both α- and β-amanitin were rapidly absorbed into the body, with times to reach peak concentration (Tmax) between 1.0 and 1.5 h. Following single oral administration at 10 mg/kg, the Cmax was significantly lower for α-amanitin (91.1 μg/L) than for β-amanitin (143.1 μg/L) (p < 0.05). The toxicokinetic parameters of α-amanitin, such as t1/2, mean residence time (MRT), and volume of distribution (Vz/F) and of β-amanitin, such as Vz/F, were significantly different (p < 0.05) when combined administration was compared to single administration. Tissues collected at 24 h after po administration revealed decreasing tissue distributions for α- and β-amanitin of intestine > stomach > kidney > lung > spleen > liver > heart. The substantial distribution of toxins in the kidney corresponds to the known target organs of amatoxin poisoning. The content in the stomach, liver, and kidney was significantly higher for of β-amanitin than for α-amanitin at 24 h following oral administration of a 10 mg/kg dose. No significant difference was detected in the tissue distribution of either amatoxin following single or combined administration. After po administration, both amatoxins were primarily excreted through the feces. Our data suggest the possibility of differences in the toxicokinetics in patients poisoned by mushrooms containing both α- and β-amanitin than containing a single amatoxin. Continuous monitoring of toxin concentrations in patients’ blood and urine samples is necessary in clinical practice.

Kinetic modeling of 18 F-PI-2620 binding in the brain using an image-derived input function with total-body PET.

Accurate quantification of tau binding from 18 F-PI-2620 PET requires kinetic modeling and an input function. Here, we implemented a non-invasive Image-derived input function (IDIF) derived using the state-of-the-art total-body uEXPLORER PET/CT scanner to quantify tau binding and tracer delivery rate from 18 F-PI-2620 in the brain. Additionally, we explored the impact of scan duration on the quantification of kinetic parameters. Total-body PET dynamic data from 15 elderly participants were acquired. Time-activity curves from the grey matter regions of interest (ROIs) were fitted to the two-tissue compartmental model (2TCM) using a subject-specific IDIF derived from the descending aorta. ROI-specific kinetic parameters were estimated for different scan durations ranging from 10 to 90 minutes. Logan graphical analysis was also used to estimate the total distribution volume (V T ). Differences in kinetic parameters were observed between ROIs, including significant reduction in tracer delivery rate (K 1 ) in the medial temporal lobe. All kinetic parameters remained relatively stable after the 60-minute scan window across all ROIs, with K 1 showing high stability after 30 minutes of scan duration. Excellent correlation was observed between V T estimated using 2TCM and Logan plot analysis. This study demonstrated the utility of IDIF with total-body PET in investigating 18 F-PI-2620 kinetics in the brain.

O-013 Population pharmacokinetics of follitropin delta during ovarian stimulation

Abstract Study question Which patient characteristics affect serum follicle stimulating hormone (FSH) concentrations in women undergoing ovarian stimulation (OS) with follitropin delta, a human cell line derived FSH? Summary answer Body weight is the main determinant of serum FSH concentrations during OS. Renal function, race, ethnicity, hepatic function and age have at most small influence. What is known already The pharmacokinetics of FSH have been studied in dedicated studies with serial blood sampling, typically conducted in healthy subjects. Such studies are designed to provide detailed pharmacokinetic profile information but lack the statistical power for identifying individual patient characteristics affecting FSH exposure. Population pharmacokinetic modelling enables evaluating the influence of patient characteristics based on few FSH measurements per patient if data from many patients are available. Study design, size, duration Serum FSH concentrations were assessed by immunoassay in seven randomized, controlled, blinded, multicentre trials of follitropin delta in women undergoing an assisted reproductive technology program. The trials were conducted in the United States, Canada, Europe, Brazil, and Asia. In all, 2,721 women treated with follitropin delta contributed to the evaluation with 6,952 FSH measurements. Participants/materials, setting, methods FSH concentrations were described with a pre-specified one-compartment population pharmacokinetic model. The key model parameters were the apparent total clearance (CL/F) of follitropin delta, the interindividual variability in CL/F and the effects of baseline values of body weight, age, race, ethnicity, renal and hepatic function on CL/F. Renal function was assessed using the estimated glomerular filtration rate (eGFR) and hepatic function by alanine transaminase (ALT) and bilirubin levels. Main results and the role of chance Area under the FSH concentration-time curve during a dosing interval (AUC) was derived from dose and CL/F. Body weight had the most pronounced effect on AUC, both in terms of effect magnitude and statistical significance. AUC was 1.28-fold higher (90% confidence limits: 1.25; 1.30) in women with a body weight of 47 kg (5th percentile) compared to women with a median body weight of 62 kg. The effect estimates of eGFR, Asian race and Black race on CL/F were within the bioequivalence limits of 0.80 and 1.25, but with 90% confidence limits not including a value of 1. The effect of Black race was estimated to be a 1.19 fold (90% confidence limits: 1.12; 1.26) higher AUC, as compared to White race. Despite this, the individual estimates of AUC were close to identical comparing these patient populations (mean (SD) relative to a typical study participant: 1.00 (0.25) and 0.97 (0.23), respectively). This is likely due to the mean body weight being higher in Black trial participants compared to White trial participants (78.3 kg compared to 68.2 kg). The effects of age, ethnicity and the hepatic function markers ALT and bilirubin were well within the bioequivalence range of 0.80 – 1.25. Limitations, reasons for caution Potential effects of subject characteristics on PK parameters such as subcutaneous absorption rate or volume of distribution could not be evaluated due to the number of serum FSH concentration measurements available per patient. Wider implications of the findings After follitropin delta administration, serum FSH concentrations are inversely related to body weight; this may be helpful for determining whether there is a need to consider body weight when selecting dose. Trial registration number NCT01426386, NCT02309671, NCT01956110, NCT03228680, NCT03296527, NCT03740737, NCT03738618, NCT03809429

Monocyte distribution width as a promising biomarker for differential diagnosis of chronic hepatitis, cirrhosis, and hepatocellular carcinoma.

We aimed to investigate the association and diagnostic value of monocyte distribution width (MDW) for chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). MDW levels were measured in 483 individuals (103 CHB, 77 LC, 153 HCC, and 150 controls). MDW was detected using UniCel Dx900 for specific cell volume parameters and the distribution of cell volumes. Our findings revealed a dynamic upward change in MDW levels across different stages of chronic liver disease, from CHB to LC and HCC. In CHB, MDW levels were highest among HBeAg-positive CHB patients and exhibited a negative correlation with HBV markers while positively correlating with ALT levels. In LC, MDW showed a positive association with the pathological progression of LC, demonstrating consistency with CP scores. MDW proved to be equally effective as traditional detection for diagnosing LC. In HCC, MDW was positively correlated with HCC occurrence and development, with higher levels observed in the high MDW group, which also exhibited elevated AFP levels, MELD scores, and 90-day mortality rates. MDW surpassed predictive models in its effectiveness for diagnosing HCC, as well as CHB and LC, with respective areas under the curve of 0.882, 0.978, and 0.973. Furthermore, MDW emerged as an independent predictor of HCC. MDW holds significant diagnostic efficacy in identifying CHB, LC, and HCC. These findings suggest that MDW could serve as a promising biomarker for predicting the severity of liver diseases and aid in rational clinical treatment strategies.

Significance of Inflammatory Markers in Primary Fibromyalgia Syndrome and Their Relation in Assessing the Disease Severity

Abstract Background Fibromyalgia syndrome (FMS) is a musculoskeletal disorder characterized by diffuse chronic musculoskeletal pain associated with various other symptoms. Although the etiology and pathogenesis of FMS are still unclear, it was reported to have possible inflammatory basis. No laboratory marker is currently available to diagnose the disease. Aim of the Work to assess the serum levels of ESR, CRP, NLR, MPV and PDW in primary Fibromyalgia syndrome patients and their relation with the disease severity and depression scores. Patients and Methods The study included 30 FMS patients, diagnosed according to the 2010 ACR (American Colleague of Rheumatology) criteria who presented to Ain Shams University Physical Medicine and Rehabilitation clinic as well as 30 healthy volunteers who served as a control group. The following laboratory tests were assessed among both groups: Erythrocyte Sedimentation Rate (ESR), C-reactive protein (CRP), Neutrophil Lymphocyte Ratio (NLR), Mean Platelet Volume (MPV) and Platelet Distribution Width (PDW). FMS patients filled out The Revised Fibromyalgia Impact Questionnaire (FIQR) and Montgomery Asberg Deprssion Score (MADRS) as well. Results MPV, NLR, ESR and CRP values were significantly higher among the patients’ group (p &amp;lt; 0.05). Statistically positive correlation was found between FIQR and each of CRP (p = 0.021) and ESR (p = 0.027) levels. Another statistically significant positive correlation was found between MADRS and CRP (p = 0.01). The NLR showed marginal positive significance with FIQR. Conclusion In the light of these previous results, we can state that the serum levels of the tested inflammatory markers being mainly the acute phase reactants, have a positive relation with disease severity and depression scores, which in turn affect the quality of daily living. Accordingly, we arise the possibility of using those markers as good indicators of ongoing inflammatory process among FMS patients reflecting the severity of the disease.

Pharmacokinetics of Human Plasma-Derived Antithrombin in Pediatric Patients Supported on Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) support of critically ill pediatric patients is associated with increased risk of thromboembolic events, and unfractionated heparin is used commonly for anticoagulation. Given reports of acquired antithrombin (AT) deficiency in this patient population and associated concern for heparin resistance, AT activity measurement and off-label AT replacement have become common in pediatric ECMO centers despite limited optimal dosing regimens. We conducted a retrospective cohort study of pediatric ECMO patients (0 to <18 years) at a single academic center to characterize the pharmacokinetics (PK) of human plasma-derived AT. We demonstrated that a two-compartment turnover model appropriately described the PK of AT, and the parameter estimates for clearance, central volume, intercompartmental clearance, peripheral volume, and basal AT input under non-ECMO conditions were 0.338 dL/h/70 kg, 38.5 dL/70 kg, 1.16 dL/h/70 kg, 40.0 dL/70 kg, and 30.4 units/h/70 kg, respectively. Also, ECMO could reduce bioavailable AT by 50% resulting in 2-fold increase of clearance and volume of distribution. To prevent AT activity from falling below predetermined thresholds of 50% activity in neonates and 80% activity in older infants and children, we proposed potential replacement regimens for each age group, accompanied by therapeutic drug monitoring.

Validation of a bioanalytical HPLC-UV method to quantify Α-Bisabolol in rat plasma applied to pharmacokinetic pilot study with the drug nanoemulsion.

α-Bisabolol (α-BIS) is a sesquiterpene alcohol present in chamomile essential oil [Chamomilla recutita (L.) Rauschert]. Despite its numerous pharmacological effects, its pharmacokinetics remain understudied. An analytical method capable of quantifying α-BIS in plasma is crucial to enable pharmacokinetic analysis. Presently, only one study has quantified it using mass spectrometry. Administering α-BIS requires a nanoemulsion for intravenous injection. This study aimed to develop and validate a bioanalytical method using high-performance liquid chromatography with an ultraviolet detector to quantify α-BIS in rat plasma. The method employed acetonitrile and ultrapure water (80:20, v/v) as the mobile phase, with a flow rate of 1ml/min and concentrations ranging from 465 to 29.625 μg/ml. All US Food and Drug Administration-designated assays were successful, indicating the method's precision, accuracy, sensitivity and linearity in determining α-BIS in rat plasma. The developed nanoemulsion, assessed through dynamic light scattering analysis, the ensemble collection of particles and polydispersity index evaluation, proved safe and effective for intravenous administration. The pharmacokinetic parameters such as volume of distribution, clearance and half-life indicated that α-BIS tends to persist in the body. This study provides a foundation for further research to explore α-BIS's potential pharmaceutical applications in the future.

Study on multifunctional magnesium copper zinc spinel ferrite nanoparticles prepared by hydrothermal route; Physical, electrical, and anti-microbial investigation

Polycrystalline spinel ferrite nanoparticles of Mg0.70-XCuXZn0.30Fe2O4(X=0.0,0.15,0.30,0.45,0.60) were prepared by hydrothermal approach. The structural modification by X-ray diffraction of Mg-Zn spinel ferrite with Cu2+ substitution was recorded through crystallite size (11–14 nm), Lattice dimension (8.34–8.38 A°), strain (7×10−3-9×10−3) and dislocation density (4×1015-7×1015) respectively. The formation of spinel structure (Fe-O) was identified by FTIR with a vibration band around 400–600 cm−1. Also, the Rietveld refined XRD pattern confirmed the presence of a cubical spinel structure. The electron microscopic (SEM) analysis revealed sphere-cubical agglomerates of the prepared material. TEM analysis revealed that the particles were inside the nanoscale range, with an average particle size of 15.97 nm determined using a lognormal histogram. The existence of the expected elements is confirmed by EDS spectra. From BET data, surface parameters including surface area (39.938–92.643 m2/gm), volume (2.355 × 10−1 to 2.52 × 10−1 gm/cm3), pore radius (5.0831–12.650 nm), and pore size distribution were determined. The magnetic parameters Ms (20–34 emu/g), Hc (30–39 Oe), and Mr (1.3–2.8 emu/g) obtained by VSM measurements indicate the single domain, pseudo single domain and multi-domain nature of as prepared nanoparticles and lower dielectric parameters at high frequency obtain from dielectric spectroscopy indicate the suitability of the material for switching devices, power application energy storage, and high-frequency applications. The antibacterial efficacy of the synthesized nanoparticles (NPs) was evaluated against different harmful bacteria and demonstrated the desired zone of inhibition (ZOI).

Model-Informed individualized dosage regimen of sirolimus in pediatric patients with intractable lymphatic malformations

Intractable lymphatic malformations (iLM) pose a significant threat to affected children, demonstrating limited responses to conventional treatments. Sirolimus, effectively inhibiting endothelial cell proliferation in lymphatic vessels, plays a crucial role in iLM treatment. However, the drug's narrow therapeutic window and substantial interindividual variability necessitate customized dosing strategies. This study aims to establish a Population Pharmacokinetic Model (PopPK model) for sirolimus in pediatric iLM patients, identifying quantitative relationships between covariates and sirolimus clearance and volume of distribution. Initial dosages are recommended based on a target concentration range of 5–15 ng/mL. Retrospective data from our institution, encompassing 53 pediatric patients with 275 blood concentration results over the past five years (average age: 4.64 ± 4.19 years), constituted the foundation of this analysis. The final model, adopting a first-order absorption and elimination single-compartment model, retained age as the sole covariate. Results indicated a robust correlation between apparent clearance (CL/F) at 5.56 L/h, apparent volume of distribution (V/F) at 292.57 L, and age. Monte Carlo simulation guided initial dosages for patients aged 0–18 years within the target concentration range. This study presents the first PopPK model using a large Therapeutic Drug Monitoring (TDM) database to describe personalized sirolimus dosing for pediatric iLM patients, contributing to pharmacokinetic guidance and potentially improving long-term clinical outcomes.

Pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid in rainbow trout (Oncorhynchus mykiss).

Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non-steroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties. The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2mg/kg in rainbow trout at 13±0.5°C. The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2mg/kg. Blood samples were taken at 13 different sampling times until the 72h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis. The elimination half-life (t1/2ʎz) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09L/kg and 0.03L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent. While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout.