Volume Of Distribution Research Articles

Mirikizumab pharmacokinetics and exposure-response in pediatric patients with moderate-to-severe ulcerative colitis.

Mirikizumab is a p19-directed anti-interleukin-23 antibody approved for the treatment of adults with moderate-to-severe ulcerative colitis (UC). Here, we report the first data of mirikizumab pharmacokinetics (PK) and exposure-response (E/R) relationships in pediatric participants (aged 2 to <18 years weighing >10 kg) with moderate-to-severe UC from the phase II, open-label study SHINE-1 (NCT04004611). PK parameters were analyzed using a model developed previously in adults with fixed-exponent allometry for body weight. Serum samples collected from 26 participants during the 12-week induction and 40-week maintenance periods of SHINE-1 were analyzed. Estimated body weight-adjusted systemic clearance, volume of distribution, and subcutaneous bioavailability were 0.021 L/h, 0.069 L/kg, and 49.8%, respectively. Covariate analysis identified no clinically significant covariates other than body weight. In the exposure range studied, E/R analysis using post hoc grouping by average concentration quartile and comparison of observed change from baseline in modified Mayo Score (MMS) at Week 12 with the adult model prediction revealed no obvious E/R relationship in clinical response, clinical remission, or endoscopic response, consistent with observations in adults. The E/R relationship for observed change from baseline in MMS at Week 12 is also similar to the adult model prediction. The PK modeling and E/R analyses suggested optimal doses of intravenous mirikizumab 300 mg for weight >40 kg, 5 mg/kg for weight ≤40 kg every 4 weeks (Q4W) during induction, and subcutaneous mirikizumab 200 mg (>40 kg), 100 mg (>20 to ≤40 kg), or 50 mg (≤20 kg) Q4W during maintenance therapy for pediatric patients with moderate-to-severe UC.

Population pharmacokinetics of caspofungin in critically ill patients receiving extracorporeal membrane oxygenation-an ASAP ECMO study.

This study aimed to describe the population pharmacokinetics of caspofungin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) and to identify dosing regimens with a high likelihood of achieving effective exposures. Serial blood samples were collected over a single-dosing interval during ECMO. Total plasma concentrations were measured by a validated chromatographic assay. A population pharmacokinetic model was built and Monte Carlo dosing simulations were performed using Monolix. The probability of target attainment (PTA) and fractional target attainment (FTA) rates were simulated for various caspofungin dosing regimens against Candida albicans, Candida glabrata, and Candida parapsilosis. In all, 64 plasma concentration-time points were obtained from 8 critically ill patients receiving ECMO. Plasma concentration-time data for caspofungin were best described by a one-compartment model with first-order elimination. Lean body weight was identified as a significant covariate of volume of distribution. The typical volume of distribution and clearance of caspofungin in this cohort were 8.13 L and 0.55 L/h, respectively. The licensed caspofungin dosing regimen (a loading dose of 70 mg on day 1 followed by a maintenance dose of either 50 mg/day or 70 mg/day) demonstrated optimal PTA rates (≥90%) against C. albicans with an MIC of ≤0.064 mg/L, C. glabrata with an MIC of ≤0.125 mg/L, and C. parapsilosis with an MIC of ≤0.064 mg/L. The FTA analysis suggested that the licensed dosing regimen is only optimal (≥95%) against Candida glabrata, regardless of lean body weight. A higher-than-standard empirical dosing regimen (e.g., a loading dose of 100 mg on day 1, followed by a maintenance dose of 100 mg daily) is likely advantageous for critically ill patients receiving ECMO.

Improving agricultural spraying with multi-rotor drones: a technical study on operational parameter optimization

Drones play a key role in enhancing nutrient management efficiency under climate change scenarios by enabling precise and adaptable spray applications. Current aerial spray application research is primarily focused on examining the influence of drone spraying parameters viz., flight height, travel speed, rotor configuration, droplet size, payload, spray pressure, spray discharge and wind velocity on spray droplet deposition characteristics. The present study aimed to study and optimize the effect of spray height, operating pressure, nozzle spacing and spray nozzle mounting configuration on spray discharge rate, spray width, spray distribution pattern, spray uniformity and spray liquid loss. A spray patternator of 5.0 m x 5.0 m was developed per Bureau of Indian Standards (BIS) standard to study the spray volume distribution pattern of boom and hex nozzle configuration. Initially, drone spray operational parameters viz., spray discharge rate (Lm−1), operating pressure (kg cm−2) and spray angle (°) were measured using digital nozzle tester, digital pressure gauge and digital protractor, respectively, in the laboratory. Then optimized the nozzle spacing for boom configuration attachment to drone sprayer and recorded best spray uniformity at 0.6 m nozzle spacing. The drone sprayer hovered at three different heights, viz., 1.0, 2.0 and 3.0 m from the top of the patternator and spray operating pressure was maintained at 4.0 kg cm−2 in outdoor condition. Single pass distribution pattern and one-direction application distribution pattern method used for optimizing height of spray, operating pressure and nozzle mounting confirmation from the results of discharge rate, spray angle, effective spray width, spray liquid loss and spray distribution uniformity. Results showed that, the better spray uniformity distribution was found when the drone sprayer hover height was increased from the top of the patternator (2.0 m). More round spray droplet vertex pattern was generated during the 1.0 m hover height compared to the 2.0 and 3.0 m hover heights due to the direct impact of downwash airflow generated by the rotors. Finally it was concluded that, the good spray volume distribution was found at 2.0 m height of spray with standard hexa nozzle configuration arrangement as compared to the boom spray nozzle arrangement.

Commentary on: The Gargano Yin Yang Breast Reduction Technique: How to Obtain Better Breast Shape, Volume Distribution, and Size With Long Lasting Results

Commentary on: The Gargano Yin Yang Breast Reduction Technique: How to Obtain Better Breast Shape, Volume Distribution, and Size With Long Lasting Results

Insights through molecular modeling into the structural requirement of Phenyl(6-phenylpyrazin-2-yl)methanone derivatives as aldose reductase inhibitors

Aldose reductase, play an important role in the pathogenesis of diabetic complications such as neuropathy, nephropathy and retinopathy. Therefore design of aldose reductase inhibitors has received considerable attention. In the present study molecular insights were explored through docking and QSAR. The quantification of the structural features of Phenyl(6-phenylpyrazin-2-yl)methanone analogs inferred that atomic Senderson electronegativity, van der Waals volume and charge distribution on the molecule are decisive for the aldose reductase inhibitory activity. Moreover, docking study depicted that benzonoid system of scaffold is crucial for - interaction with the side chain of key aromatic amino acids i.e. TRP111 and TRP20. These structural insights might provide significant roadmap for continuing search of potential ARIs prior to synthesis.

Green/red fluorescent protein disrupting drugs for real‐time permeability tracking in three‐dimensional tumor spheroids

AbstractThree‐dimensional (3D) spheroid models offer a more physiologically relevant and complex environment compared to traditional two‐dimensional cultures, making them a promising tool for studying tumor biology and drug response. However, these models often face challenges in real‐time monitoring of drug diffusion, penetration, and target engagement, limiting their predictive power for in vivo and clinical outcomes. This study introduces a novel approach for real‐time tracking of drug permeability using small molecule drugs with GFP/RFP‐disrupting properties that correlate with their efficacy. We developed a reproducible 3D spheroid model with various cancer cell lines expressing GFP/RFP for efficient drug screening. Through screening over 20 FDA‐approved enzyme inhibitors, we identified three covalent kinase inhibitors—osimertinib, afatinib, and neratinib—that irreversibly disrupt GFP and RFP fluorescence. Our results reveal distinct drug diffusion and penetration profiles within GFP/RFP‐expressing spheroids, varying with drug concentration and formulation, and correlating with clinical volume of distribution (Vd) values. Additionally, we demonstrate that our approach is useful for evaluating different drug formulations as well as screening penetration enhancers for solid tumors. These findings offer a valuable 3D model for studying kinetics of drug permeability and efficacy in tumor‐like environments, with potential implications for drug delivery research and formulation development.

18F]SF51, a novel 18F-labeled PET radioligand for translocator protein 18kDa (TSPO) in brain, works well in monkeys but fails in humans.

[18F]SF51 is a novel radioligand for imaging translocator protein 18 kDa (TSPO) that previously displayed excellent imaging properties in nonhuman primates. This study assessed its performance in human brain and its dosimetry. Seven healthy participants underwent brain PET imaging to measure TSPO binding using a two-tissue compartment model (2TCM) to calculate total distribution volume (VT). This cohort included two high-affinity binders (HABs), three mixed-affinity binders (MABs), and two low-affinity binders (LABs). Two other participants received whole-body scans to assess radiation exposure. Peak brain radioactivity reached a standardized uptake value (SUV) of 1.4 at 3 minutes post-injection, diminishing to 30% of peak by 120 minutes. The average VT for all genotype groups was notably low (<1 mL·cm-3), emphasizing the radioligand's poor binding in brain. [18F]SF51 remained sensitive to the TSPO polymorphism in vivo, as shown by a two-fold difference in VT between HABs and LABs. VT stabilization by 80 minutes post-injection suggested minimal radiometabolite accumulation in brain. The average effective dose was 13.8 ± 0.9 µSv/MBq. Contrary to previously published animal data, [18F]SF51 showed low binding to human TSPO, with uptake remaining influenced by the rs6971 polymorphism. These findings highlight the challenges of developing TSPO radioligands and underscore the significant species differences that may influence translational outcomes.ClinicalTrials.gov identifier: NCT05564429; registered 10/03/2022.

Multiscale Qualitative–Quantitative Characterization of the Pore Structure in Coal-Bearing Reservoirs of the Yan’an Formation in the Longdong Area, Ordos Basin

Accurate characterization of coal reservoir micro- and nanopores is crucial in evaluating coalbed methane storage and gas production capacity. In this work, 12 coal-bearing rock samples from the Jurassic Yan’an Formation, Longdong area, Ordos Basin were taken as research objects, and micro- and nanopore structures were characterized via scanning electron microscopy, high-pressure mercury pressure, low-temperature N2 adsorption and low-pressure CO2 adsorption experiments. The main factors controlling coal pore structure development and the influence of pore development on the gas content were studied by combining the reflectivity of specular samples from the research area, the pore microscopic composition and the pore gas content determined through industrial analyses and isothermal absorption experiments. The results show that the coal strata of the Yan’an coal mine are a very important gas source, and that the coal strata of the Yan’an Formation in the study area exhibit remarkable organic and clay mineral pore development accompanied by clear microfractures and clay mineral interlayer joints, which together optimize the coal gas storage conditions and form efficient microseepage pathways for gas. Coalstone, carbonaceous mudstone and mudstone show differential distributions in pore volume and specific surface area. The general trend is that coal rock is the best, carbonaceous mudstone is the second best, and mudstone is the weakest. The coal samples’ microporous properties are positively correlated with the coal sample composition for the specular group, whereas there is no clear correlation for the inert group. An increase in the moisture content of the air-dried matrix promotes adsorption pore development, leading to increases in the microporous volume and specific surface area. CH4 adsorption in coal rock increases with increasing pressure, and the average maximum adsorption is approximately 8.13 m3/t. The limit of the amount of methane adsorbed by the coal samples, VL, is positively correlated with the pore volume and specific surface area, indicating that the larger the pore volume is, the greater the amount of gas that can be adsorbed by the coal samples, and the larger the specific surface area is, the greater the amount of methane that can be adsorbed by the coal samples. The PL value, pore volume and specific surface area are not correlated, indicating that there is no direct mathematical relationship between them.

Anidulafungin exposure and population pharmacokinetics in critically ill patients with invasive candidiasis.

Anidulafungin is recommended as a first-line treatment for invasive Candida infections in critically ill patients. Pharmacokinetic (PK) variability is large in critically ill patients, potentially compromising pharmacokinetic-pharmacodynamic (PKPD) target attainment under standard dosing. We aimed to assess anidulafungin exposure, PKPD target attainment, and population (pop)PK in critically ill patients. Adult ICU patients receiving standard anidulafungin dosing [200mg on day 1, then 100mg daily] were included (NCT04045366). We performed rich blood sampling on an early (day 2 ± 1) and/or late (day 5 ± 1) treatment day. Using total anidulafungin plasma concentrations, we developed a popPK model (NONMEM7.5) and conducted Monte Carlo simulations (n = 1,000 per virtual patient) to evaluate the impact of patient factors on PKPD target attainment (AUC24h target 83.5mg×h/L). Twenty patients contributed 188 anidulafungin concentrations. PKPD target attainment was 45% and 65% on early and late sampling days, respectively. A two-compartment popPK model with first-order elimination described the data. Anidulafungin clearance increased with bodyweight and central volume of distribution increased as serum albumin decreased. Both bodyweight and serum albumin had a clinically relevant impact on PKPD target attainment at day 1 (area under the ROC curve; AUROC 0.82 and 0.62, respectively), and bodyweight on PKPD target attainment at day 14 (AUROC 0.94). Standard anidulafungin dosing regimen fails to achieve adequate target attainment throughout the treatment period. Standard anidulafungin dosing is insufficient for achieving adequate exposure in critically ill patients. An interactive simulation tool is provided to aid dose-finding research and explore different dosing strategies and targets.

Model-informed precision dosing of quetiapine in bipolar affective disorder patients: initial dose recommendation.

Bipolar affective disorder (BAD) is a mood disorder with high morbidity and mortality. Quetiapine can be used in the treatment of patients with BAD; however, the precise administration regimen of quetiapine in these patients is still unknown. In this study, a population pharmacokinetic (PPK) model of quetiapine in patients with BAD was constructed based on model-informed precision dosing (MIPD) and real-world clinical data and an optimal initial dose of quetiapine in these patients was recommended. A total of 99 patients with BAD treated with quetiapine were included. At the same time, the quetiapine concentrations, the physical and chemical indices of the patients, and the drug combination information were collected. A quetiapine PPK model for patients with BAD was then constructed and an initial dose based on Monte Carlo simulation was recommended. In the final model of quetiapine for patients with BAD, the apparent oral clearance (CL/F) and the apparent volume of distribution (V/F) were 76.1 L/h and 530 L, respectively. For patients with BAD weighing 40-66 kg, the initial dose recommendation was 16 mg kg-1 day-1, the probability of reaching the therapeutic window was 78.8%-82.2%, and the probability of exceeding the upper limit of the therapeutic window was 5.2%-10.3%. For patients with BAD weighing 66-120 kg, the initial dose recommendation was 12 mg kg-1 day-1, the probability of reaching the therapeutic window was 81.5%-85.5%, and the probability of exceeding the upper limit of the therapeutic window was 3.6%-8.1%. The present study, for the first time, recommended an initial dose of quetiapine in patients with BAD based on MIPD and real-world data, providing an individualized reference for the administration of quetiapine in these patients.

Determination of pharmacokinetic-pharmacodynamic cutoff values of oxytetracycline in calves and adult cattle using population pharmacokinetic modeling.

A harmonized clinical breakpoint for interpreting antimicrobial susceptibility testing of oxytetracycline in cattle is currently lacking in Europe. This study aimed to establish a pharmacokinetic/pharmacodynamic (PK/PD) cutoff to propose clinical breakpoints, facilitating reliable interpretation of antimicrobial susceptibility results in cattle. A meta-analysis of oxytetracycline pharmacokinetic data from 69 cattle was conducted, including 1,730 plasma concentration samples from animals administered 20 mg/kg intramuscularly and/or 20 or 40 mg/kg intravenously. A three-compartment model with two absorption phases was selected, incorporating age as a covariate for clearances and distribution volumes. The PK/PD cutoff was defined as the maximum MIC for which the fAUC/MIC index achieves the pharmacodynamic target in 90% of cattle given the standard dosing regimen. The pharmacodynamic index (PDI) target selected was established to 24 h, i.e., the average free plasma concentration of oxytetracycline over the 24-h dosing interval, under steady-state conditions, is equal to the selected MIC. Simulations indicated a PK/PD cutoff of 2 mg/L in adult cattle and 1 mg/L in calves for intramuscularly administered long-acting products at 20 mg/kg with a 48-hour efficacy duration. The difference is attributed to higher clearance rates in calves. The established PK/PD cutoffs, when used alongside the wild-type bacterial epidemiological cutoff, can aid in setting clinical breakpoints for oxytetracycline, supporting effective antimicrobial therapy in cattle and accounting for age-related pharmacokinetic differences.

Does a carboxamide moiety alter the toxicokinetics of synthetic cannabinoids? A study after pulmonary and intravenous administration of cumyl-5F-P7AICA to pigs.

Synthetic cannabinoids (SCs) are consumed as an alternative to cannabis. Novel compounds are developed by minor modifications in their chemical structure, e.g. insertion of a carboxamide moiety as a linker, which can potentially lead to altered toxicokinetics (TK). Knowledge on the TK data of SCs, especially structural modified substances, is scarce. Hence, interpretation of toxicological results is challenging. Therefore, the aim of the present study was to evaluate the TK of cumyl-5F-P7AICA in a pig model, which was shown to be suitable for TK studies of SCs. A 200µg/kg body weight dose of cumyl-5F-P7AICA was administered intravenously (n = 6) or inhalatively (n = 10) via an ultrasonic nebulizer to pigs. Blood specimens were repeatedly drawn over 6h and the concentrations of cumyl-5F-P7AICA as well as its N-pentanoic acid (NPA) metabolite were determined using a fully validated LC-MS/MS method. Based on the concentration-time profiles, a population TK analysis yielded a three-compartment model for the TK of cumyl-5F-P7AICA, whilst a two-compartment model described the NPA best. The incorporation of transit compartments accounts for the time delay between the appearance of cumyl-5F-P7AICA and NPA in serum. Finally, the model was upscaled to humans using allometric scaling. In comparison to older SCs, a higher volume of distribution was determined for cumyl-5F-P7AICA. No further relevant differences of the TK properties were observed. Insertion of a carboxamide moiety into the chemical structure of SCs does not appear to have only minor influence on the TK.

The State of the Art in Post-Mortem Redistribution and Stability of New Psychoactive Substances in Fatal Cases: A Review of the Literature

In post-mortem (PM) investigations, forensic toxicologists attempt to identify legal or illegal substances present before death and determine how they contributed to the cause of death. A critical challenge is ensuring that PM sample concentrations accurately reflect those at the time of death, as postmortem redistribution (PMR) can alter these levels due to anatomical and physiological changes. The PMR phenomenon is called a ‘toxicological nightmare’. PMR significantly affects post-mortem drug concentrations, particularly for lipophilic drugs and those with a high volume of distribution. The emergence of new psychoactive substances (NPSs) has led to a growing recognition of their role as a significant public health concern, frequently associated with fatalities related to polydrug use. These substances are renowned for their ability to induce intoxication at low doses, which has led to the continuous updating of toxicological and forensic methods to improve detection and adopt new analytical standards. The comprehensive detection of NPS metabolites, some of which are still undiscovered, presents an additional analytical challenge, as do their metabolic pathways. This complicates their identification in fatal cases using standard analytical methods, potentially leading to an underestimation of their actual prevalence in toxicological results. Furthermore, the interpretation of analytical results is hindered by the absence of data on PM blood levels and the specific contributions of NPS to causes of death, exacerbated by the lack of knowledge of whether the PMR phenomenon influences them. This paper presents a comprehensive review of the literature on post-mortem cases involving various NPS, categorized according to classifications by the United Nations Office on Drugs and Crime (UNODC) and the European Union Drugs Agency (EUDA). These categories include cathinones, phenylethylamines, arylalkylamines, phencyclidine-type substances, phenmetrazines, piperazines, phenidates, aminoindanes, LSD-like NPSs, tryptamines, fentanyl analogs, designer benzodiazepines, synthetic cannabinoids, and nitazenes. This review covers not only postmortem blood levels but also the stability of the substances studied, the methods of analysis, and attempts to shed some light on the PMR phenomenon. This review used various key terms, such as PMR, NPS, and the names of previously categorized substances and drug analyses across multiple peer-reviewed journals and databases, including Scopus, Google Schoolar, Springer, PubMed, and Wiley Online Library. In addition, references from retrieved articles were examined to identify additional relevant research. Interpreting post-mortem toxicological results is complex and lacks definitive guidelines, requiring a nuanced understanding of its challenges and potential pitfalls. As a result, post-mortem toxicology is often regarded as an art. The primary aim of this review is to provide forensic toxicologists with a comprehensive framework to assist in the evaluation and interpretation of NPS analysis. This guide is intended to complement the existing knowledge and practices applied in forensic laboratories within the toxicological analysis of post-mortem cases.

Integrating of In Silico and In Vitro Approaches to Determine Biological Activities of Abelmoschus esculentus’s Seeds

The purpose of this study was to examine the antioxidant, anti-urease, and anticholinesterase properties of extracts from plant seeds, as well as their toxicity on normal cells. In addition, the goal of this work was to use an in silico and in vitro method to evaluate the biological activity and mechanism of action of A. esculentus. DPPH (2,2-diphenyl-1-picrylhydrazyl), CUPRAC (Cupric ion reducing antioxidant capacity), and FRAP (Ferric reducing antioxidant power) techniques were used to examine the antioxidant properties of plant extracts. The extracts' anticholinesterase, anti-urease, and cytotoxic activity were determined using the Ellman, Indophenol, and MTT techniques, respectively. Computer algorithms were used to estimate ADMET and molecular docking techniques for compounds in plant. When the antioxidant activity results were examined, it was determined that water (IC50:0.313 mg/mL) and ethanol (IC50:0.314 mg/mL) extract showed DPPH activities close to each other. It was determined that the water (7.780mM FeSO4/mg extract, 1.106 mM troloxE/mg extract) extract showed higher activity than the ethanol (3.420 mM FeSO4/mg extract, 0.343 mM troloxE/mg extract) extract in FRAP and CUPRAC experiments. Considering the enzyme inhibition results, it was determined that the water extract showed the highest anti-urease activity, while the ethanol extract showed the highest anticholinesterase activity. It was also determined that both extracts had no toxic effect on normal cell lines (L-929). Based on pkCSM values, procyanidin B1 and procyanidin B2 compounds have a low volume of distribution, whereas rutin and quercetin compounds have a high volume of distribution (VDss). Not all compounds were predicted to have mutagenic and hepatotoxicity effects. In terms of score and ligand efficiency, procyanidin B1, procyanidin B2, quercetin, and rutin compounds appear to be superior to the reference. The chemicals quercetin and procyanidin B2 are thought to be key players in the pathophysiology of oxidative stress. In this study, the fact that the seeds’ extracts have biological activity and have no toxic effects on normal cell lines suggests that the seeds can be used medicinally and nutritionally in the future.

Test-Retest performance of [18F]MK-6240 tau burden and relative delivery indices in cognitively normal older subjects using PET/MRI

Abstract Accurate interpretation of quantitative PET outcomes hinges on understanding the test-retest variability (T-RT). Previous studies of the tau-PET ligand [18F]MK-6240 reported adequate T-RT performance of tau burden estimates over a short-term 21-day and over a longer-term 6-month T-RT period, primarily involving Alzheimer’s disease (AD) and cognitively normal (CN) subjects, respectively. However, several T-RT characteristics have not yet been reported, particularly in older CN (oCN) subjects. Here, we investigate the short-term T-RT performance of dynamic [18F]MK-6240 outcomes in a group largely consisting of oCN. We report T-RT for uptake in potential reference regions, for extracerebral off-target signal, and for estimates of tau burden and relative delivery indices in tau-bearing target regions. Eight participants (7 oCN, 1 AD) underwent baseline dynamic [18F]MK-6240 PET/MRI (Biograph mMR) and a retest follow-up PET/MRI scan within approximately 3 weeks. T-RT was evaluated using absolute percentage differences and intraclass correlation coefficients (ICC) in three groups of regions: 1) potential reference regions using standardized-uptake-values 90-110 minutes post-injection (SUV90-110min); 2) target regions using SUV ratios (SUVR90-110min), distribution volume ratios (DVR), and relative delivery (R1); and 3) extracerebral region using SUVR90-110min. A voxel-based partial volume correction (PVC) was applied. T-RT was evaluated with and without PVC. In oCN subjects, the SUV90-110min T-RT in the evaluated reference regions ranged from 6-11% (ICC &amp;gt; 0.9); target region T-RT was similar for SUVR90-110min (4-9%, ICC: 0.62-0.97), DVR (3-10%, ICC: 0.66-0.92), and R1 (3-14%, ICC: 0.52-0.97). PVC had minimal impact on reference region SUV90-110min T-RT, but increased target region T-RT variability (SUVR90-110min: 10-26%; DVR: 6-22%; R1: 4-20%). Extracerebral SUVR90-110min exhibited higher T-RT variability (~12%, ICC: 0.85) than other target regions (average 6%) and increased to ~15% after PVC. Our findings are consistent with previous reports and provide further evidence of acceptable [18F]MK-6240 T-RT in low-signal oCN subjects. Our results suggest [18F]MK-6240 is suitable for detecting early tau deposition and longitudinal changes over time, and further support the viability of [18F]MK-6240 R1 to evaluate longitudinal changes in perfusion. PVC increased T-RT variability in tau burden and R1 outcomes. Notably, the extracerebral signal exhibited higher T-RT variability than other target and reference regions and may affect their signal.

Population pharmacokinetic analysis identifies an absorption process model for mycophenolic acid in patients with renal transplant.

The pharmacokinetics (PKs) of mycophenolic acid (MPA) exhibit considerable complexity and large variability. We developed a population pharmacokinetic (popPK) model to predict the complex PK of MPA by examining an absorption model. Forty-two patients who had undergone renal transplantation were included in this study. popPK analysis, incorporating several absorption models, was performed using the nonlinear mixed-effects modeling program NONMEM. The MPA area under the concentration-time curve at 0-12 h (AUC0-12) was simulated using the final model to calculate the recommended dose. The PK of MPA was adequately described using a two-compartment model incorporating sequential zero- and first-order absorption with lag time. Total body weight, renal function (RF), and posttransplantation day (PTD) were included as covariates affecting MPA PK. The final model estimates were 7.56, 11.6 L/h, 104.0 L, 17.3 L/h, 169.0 L, 0.0453, 0.283, and 1.95 h for apparent nonrenal clearance, apparent renal clearance, apparent central volume of distribution, apparent intercompartmental clearance, apparent peripheral volume of distribution, absorption half-life, lag time, and duration of zero-order absorption, respectively. Simulation results showed that a dose regimen of 500-1000 mg twice daily is recommended during the early posttransplantation period. However, dose reduction could be required with increased PTD and decreased RF. The complex PK of MPA was explained using an absorption model. The developed popPK model can provide useful information regarding individual dosing regimens based on PTD and RF.

Favipiravir pharmacokinetics in Thai adults with mild COVID-19: A sub-study of interpatient variability and ethnic differences in exposure.

This sub-study sought to characterize the pharmacokinetics (PK) of favipiravir (FPV) within Thai adults and quantitatively assess differences in exposure to those previously reported in other populations as a basis to understand putative differences in efficacy between studies conducted in different regions. It was nested within a prospective trial of adults with symptomatic COVID-19 infection without pneumonia receiving 1800 mg FPV twice-daily on day 1 and 800 mg twice-daily thereafter. Individual PK profiles were fitted with a one-compartment disposition model (first-order absorption). Eight adults (seven female) with a median age of 39 years and BMI of 27.9 kg/m2 were included. Seven adults achieved plasma concentrations above the EC90 invitro target (25 mg/L), with minimum-maximum concentrations decreasing with repeat dosing. The mean FPV apparent clearance observed in this study was 1.1 L/h (coefficient of variation [CV]: 60%), apparent volume of distribution 20.6 L (CV: 40%), absorption rate constant 6.1 h (CV: 100%), and 2.4 daily % change in apparent clearance (CV: 315%). Higher exposures were observed in these Thai adults compared with data from previous studies in Chinese, Japanese, and Turkish populations, respectively. Current FPV doses recommended in Thailand achieved target plasma concentrations with higher exposures than those described previously in other populations. The limited sample size prohibits firm conclusions from being drawn but the presented data warrants confirmation with a view to interrogate the appropriateness of doses used in randomized clinical trials that failed to demonstrate efficacy.

Interdiffusion Induced Changes in the Absorption Spectra of III-V Quantum Dot Systems

III-V Semiconductor quantum dots (QDs) grown with growth interruption technique do not have uniform group III composition inside the dot. Modelling such as-grown structures requires in-depth knowledge of the composition and potential well profile. In this work, we have developed a three-dimensional analytical model which incorporates strain, as well as the variation of group III composition profile in both lateral and vertical directions inside an as-grown QD in order to quantify the effect of dot size variation on the interband optical absorption spectra of as-grown QD systems. Earlier reports on this subject considered the variation of either the dot height or base to account for the size deviation, which may not be sufficient enough to predict the dot size distribution in realistic systems, where all dimensions are likely to suffer from deviation. Keeping this in mind, Gaussian distribution of dot volume has been adopted here to consider the variations of height and base of QDs in a cumulative way. In our study, we considered InGaAs/GaAs and InGaN/GaN QD systems. The non-uniform distribution of indium inside the as-grown dot leads to a non-rectangular potential well profile, which eventually transforms into a rectangular one after annealing. Through the proposed model, we have investigated the effect of inhomogeneous indium composition and dot size variation on the optical absorption spectra of InGaAs/GaAs and InGaN/GaN as-grown QD systems through Gaussian distribution of dot volume. We have also discussed the effect of size deviation on the full width at half maxima (FWHM) of both as-grown and annealed QD systems. Emphasis has been given to the changes in the conduction and valence band potential profiles due to changes in the morphology inside the dot leading to subsequent changes in the energy levels caused by composition uniformity due to annealing and interdiffusion, thus modifying the nature of absorption spectra.

Pharmacokinetics and brain uptake of sodium selenate and selenium in naïve rats and a lateral fluid percussion injury ratmodel.

Post-traumatic epilepsy (PTE) is a life-long complication of traumatic brain injury (TBI). The development of PTE is associated with neurological morbidity and increases the risk of mortality. An aim of EpiBioS4Rx (Epilepsy Bioinformatics Study for Antiepileptogenic Therapy) was to test potential therapies to prevent the development of PTE in the lateral fluid percussion injury (LFPI) rat model of TBI, in which rats were subjected to injury at the left parietal cortex. Sodium selenate has been reported to be antiepileptogenic post-TBI in rodent models by activating protein phosphatase 2A and reducing phosphorylated tau (p-tau) protein. We aimed to characterize the pharmacokinetics (PK) and brain uptake of sodium selenate using naïve control and LFPI rats. Rats received either a single bolus dose or a single bolus dose followed by a 7-day subcutaneous minipump infusion of sodium selenate. Sodium selenate and selenium concentrations in plasma and brain were analyzed and used for PK estimation and brain exposure assessment. Selenium concentrations rapidly increased after sodium selenate administration, demonstrating biotransformation from sodium selenate to selenium. Sodium selenate and selenium PK parameters were estimated using non-compartmental analysis. Sodium selenate clearance (CL/F) and volume of distribution (Vd/F) varied by dose and route of administration, suggesting differences in bioavailability and nonlinear pharmacokinetics at the doses tested. Brain-to-plasma partition coefficients (AUCbrain/AUCplasma) for sodium selenate and selenium were found to be 0.7-1.3 and 0.1-0.3 following single-dose injection, respectively, indicating active transport of sodium selenate across the blood-brain barrier (BBB).

Influence of the prebiotic Immunobeta and the combination Immunobeta + Zoovit probiotic on haematological parameters in breed Ile-de-France lambs

Abstract. The aim of the study was to evaluate the effect from supplementation of the prebiotic Immunobeta and the probiotic Zoovit on haematological parameters in Ile-de-France lambs. The experiment was conducted in the experimental farm of the Agricultural Institute, Stara Zagora. A total of 45 lambs divided into 3 groups of 15 animals each with similar initial live body weight, sex and birth type were included – one control and two experimental. Each animal from experimental group I was supplemented once daily with 8 g prebiotic Immunobeta and those from experimental group II received the same amount of the prebiotic plus 4 g probiotic Zoovit. Blood samples for analysis were collected from 8 animals per group in the beginning and the end of the trial. The group supplemented with the combination Immunobeta + Zoovit had statistically significantly higher haemoglobin content (P&lt;0.05) and haematocrit (P=0.013) that the group fed a diet with Immunobeta prebiotic. The mean corpuscular volume was lower (P&lt;0.05) in experimental group I vs. controls. The addition of the Immunobeta prebiotic resulted in reduced haemoglobin (Р=0.012), haematocrit (Р=0.012), mean corpuscular volume (Р&lt;0.001), mean corpuscular haemoglobin concentration (Р&lt;0.001), mean platelet volume (Р=0.002), platelet distribution width (Р=0.001) and volume of platelet participation (Р=0.002) at the end of the trial period. After the supplementation with synbiotic, there was a trend towards lower haemoglobin content (Р=0.088). The Immunobeta + Zoovit addition to the diet resulted in statistically significantly reduced haematocrit (Р&lt;0.05), reduced mean corpuscular volume, mean corpuscular haemoglobin concentration, mean platelet volume (Р&lt;0.001), platelet distribution width (Р&lt;0.01) and volume of platelet participation levels (Р&lt;0.05).