Volume Of Distribution Research Articles

Development of a Web Application for Simulating Plasma Drug Concentrations in Patients with Zolpidem Intoxication.

Zolpidem is a widely prescribed hypnotic Z-drug used to treat short-term insomnia. However, a growing number of individuals intentionally overdose on these drugs. This study aimed to develop a predictive tool for physicians to assess patients with zolpidem overdose. A population pharmacokinetic (PK) model was established using digitized data obtained from twenty-three healthy volunteers after a single oral administration of zolpidem. Based on the final PK model, a web application was developed using open-source R packages such as rxode2, nonmem2rx, and shiny. The final model was a one-compartment model with first-order absorption and elimination with PK parameters, including clearance (CL, 16.9 L/h), absorption rate constant (Ka, 5.41 h-1), volume of distribution (Vd, 61.7 L), and lag time (ALAG, 0.394 h). Using the established population PK model in the current study, we developed a web application that enables users to simulate plasma zolpidem concentrations and visualize their profiles. This user-friendly web application may provide essential clinical information to physicians, ultimately helping in the management of patients with zolpidem intoxication.

Impacts of permeability and effective diffusivity of porous scaffolds on bone ingrowth: In silico and in vivo analyses

The permeability and the effective diffusivity of a porous scaffold are critical in the bone-ingrowth process. However, design guidelines for porous structures are still lacking due to inadequate understanding of the complex physiological processes involved. In this study, a model integrating the fundamental biological processes of bone regeneration was constructed to investigate the roles of permeability and effective diffusivity in regulating bone deposition in scaffolds. The in silico analysis results were confirmed in vivo by examining bone depositions in three diamond lattice scaffolds manufactured using selective laser melting. The findings show that the scaffolds with better permeability and effective diffusivity had deeper bone ingrowth and greater bone volume. Compared to permeability, effective diffusivity exhibited greater sensitivity to the orientation of porous structures, and bone ingrowth was deeper in the directions with higher effective diffusivity in spite of identical pore size. A 4.8-fold increase in permeability and a 1.6-fold increase in effective diffusivity by changing the porous structure led to a 1.5-fold increase in newly formed bone. The effective diffusivity of the porous scaffold affects the distribution of osteogenic growth factor, which in turn impacts cell migration and bone deposition through chemotaxis effects. Therefore, effective diffusivity may be a more suitable indicator for porous scaffolds because our study shows changes in this parameter determine changes in bone distribution and bone volume.

Selected Chromatographic Methods for Determining the Biological Activity of Substances

This paper presents various aspects of the use of chromatography to determine the biological activity of substances. On the one hand, the use of chromatography to determine the lipophilicity of a substance, a property that affects all LADME steps in various biomimetic systems, is presented, using various descriptors such as the retention factor in pure water (or buffer with physiological plasma pH), the CHI value, and Chrom logD. The use of chromatography in biomimetic systems to determine the interaction of substances with phospholipids (IAM stationary phases) and transport proteins (stationary phases with immobilised proteins) is also discussed. On the basis of the retention data obtained in these systems, the volume of distribution of the substance and the degree of binding of the substance with the proteins in question can be determined. Chromatography is also a method used to determine the interaction of substances with specific membrane receptors at their site of action using membrane chromatography (MCM). Thanks to biological detection, chromatography can also be used to determine the antimicrobial activity (bioautography) of substances and the effect of substances on biochemical reactions taking place in organisms, such as antioxidant properties and the inhibitory activity of various enzymes (biological assay).

Uncertain programming model for designing multi-objective reverse logistics networks

Given the contradiction between the rapid growth of products and the modest recovery rate of end-of-life products, there is a pressing need to understand the societal significance of establishing a reverse logistics network for end-of-life products. This research constructs an open-loop five-tier reverse logistic network model encompassing customers, centres for collection, disassembly and inspection, remanufacturing, and disposal. A multi-objective mixed-integer nonlinear programming model under uncertainty has been developed. Unlike previous research, this model accounts for surrounding residents' disutility of facilities while simultaneously minimizing economic costs and environmental impact. Besides, uncertainty theory is introduced in solving the proposed model. More specifically, the formulated model converts all uncertain variables into uncertain distributions by implementing the uncertain multi-objective programming method. Furthermore, a customised non-dominated sorting genetic algorithm III (NSGA-III) is proposed and is employed for the first time to address facility selection and recycling volume distribution within the network. The model is then validated using a real-life case study focusing on end-of-life vehicles in Changchun, China. This research could assist decision-makers in both governmental and private sectors in achieving a balanced approach to the interests of the economy, environment, and local communities comprehensively when designing reverse supply chains.

Research on Vegetables Sales Profit Based on Machine Learning

The sales volume of different vegetables in supermarkets is different, and the profit is different. The research on the profit of each category of vegetables can help supermarkets predict the sales revenue more accurately to improve inventory management, purchasing plans, and sales strategy. This can help the supermarket avoid excess or insufficient inventory, improve profits, and help the supermarket identify potential sales risks. The research team obtained daily sales data for various categories of vegetables from a supermarket on the Internet for some time. First, according to the "cost plus pricing" method of vegetables, regression analysis was conducted on the total cost and total profit of various categories of vegetables, and it was found that there was a strong linear relationship, and the profit rate of various categories of vegetables was relatively fixed. They were [0.6629, 0.5915, 0.4663, 0.5121, 0.5596, 0.5381]. Since the sales volume of vegetables has seasonal characteristics, this paper established the ARIMA model to forecast the sales volume of each category of vegetables; and obtained the sales volume distribution of each category of vegetables from July 1 to 7, 2023. The BP neural network model with 22 layers of hidden layers was established, and the purchase unit price data could be obtained according to the known sales data. The R square of the model was greater than 0.7, and the goodness of fit was high. According to the known correlation, considering the impact of the loss rate on the profit and the rationality of the data, a multivariate linear programming model is established to give the replenishment volume and pricing strategy from July 1 to 7, 2023. It is concluded that the maximum profit of the supermarket in these seven days is [845.1835, 870.5028,861.6210, 858.8551, 839.4595, 864.7580, 892.9897]. Through the sensitivity analysis of the profit rate of each category of vegetables, it is concluded that the profit rate increases by 1%, the income will increase by about 1.1%, and the model is robust.

Gentamicin concentration and acute kidney injury in term neonates treated for neonatal sepsis with gentamicin and ampicillin-cloxacillin combination.

Gentamicin is widely used to treat neonatal infections caused by both Gram-negative and Gram-positive bacteria, and the WHO recommends its use while monitoring serum creatinine and gentamicin concentrations to avoid drug-induced nephrotoxicity and ototoxicity. Yet in some resource-limited settings, the drug is used without monitoring. A population pharmacokinetics study involving term neonates with neonatal infection admitted to a neonatal unit. Participants were started on intravenous gentamicin 5 mg/kg once a day in combination with ampicilin-cloxacillin. Blood samples for serum gentamicin concentration were taken at 0.25, 0.5, 1, 2, 3, 5, 6, 8, 10, 12, 14, 16, 18, 20, 23, and 24 hours after the initial dose, each participant contributing two samples to the 24 hour sampling schedule. An additional sample for trough concentration was taken from each participant just before the third gentamicin dose while serum creatinine concentration was measured before and after treatment. Twenty-four participants were enrolled into the study and included in the final analysis. Mean (SD) peak and trough serum gentamicin concentrations were 16.66 (0.64) µg/mL and 3.28 (0.70) µg/mL, respectively. Gentamicin clearance (CL) was 0.40 mL min-1 kg-1 and volume of distribution (VD) was 0.31 L kg-1. Mean (SD) serum creatinine level after treatment was 209.7 (70.4) µmol/L compared to 103.3 (23.6) µmol/L before treatment [mean difference (106.4 ± 67.1; 95% confidence interval (CI): 78.1; 134.7 µmol/L; t (23) = 7.77; P < 0.001]. All participants fulfilled the Kidney Disease Improving Global Outcomes (KDIGO) criteria for acute kidney injury after treatment. Treatment of neonatal infection with antimicrobial regimen containing gentamicin, without renal function and gentamicin concentration monitoring, carries a significant risk for drug-induced acute kidney injury.

Hourglass cascaded recurrent stereo matching network

Stereo matching acts a crucial role in computer vision and robotics applications. An accurate cost volume and robust disparity regression method are essential for stereo matching of high accuracy. Following GCNet and PSMNet, constructing 4D cost volume and then using the soft argmin method to regress has been dominated. However, it will encounter many difficulties due to the multi-modal distribution of cost volume. One of the reasons for this multi-modal distribution is the occlusion area which not be possible to find a matching region on the reference image and rarely discussed. In this paper, we propose to use global context information could improve the performance of model in occluded regions. Recently, novel recurrent neural network regression methods are proposed, but most of them regress disparity maps from 3D cost volume. In this paper, we propose the new combinatorial paradigm that combine stacked hourglass modules and recurrent neural networks to further aggregate 4D cost volume and regress disparity respectively. The proposed method can be seamlessly integrated into most stereo matching networks, we improved the accuracy by 45% for PSMNet and 38% for GwcNet in our experiment. Experimental results on Scene Flow, KITTI2012, KITTI2015, and ETH3D datasets show our method is competitive. The code is available at: https://github.com/truman1211/HCRnet.

Preclinical pharmacokinetic studies of villocarine A, an active Uncaria alkaloid.

Villocarine A is a bioactive indole alkaloid isolated from the Uncaria genus. It has demonstrated vasorelaxation activity and potential to protect the central nervous system. To identify the pharmacokinetic properties of villocarine A, a series of in vitro and in vivo studies have been performed. Villocarine A was found to be highly permeable (15.6 ± 1.6*10-6cm/s) across human colorectal adenocarcinoma cell monolayer with high protein binding (>91%) in both rat and human plasma. Hepatic extraction ratio of villocarine A was 0.1 in pooled rat liver and 0.2 in human liver microsomes and was found stable in rat plasma at 37°C. Due to the high permeability and low rate of metabolism properties, villocarine A was initially considered suitable for preclinical development and an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification (linearity: 1-150 ng/ml) in rat plasma was developed and validated for in vivo studies. Essential pharmacokinetic parameters included the volume of distribution and clearance of villocarine A, which were found to be 100.3 ± 15.6L/kg and 8.2 ± 1.1L/h/kg, respectively, after intravenous administration in rats. Following oral dosing, villocarine A exhibited rapid absorption as the maximum plasma concentration (53.2 ± 10.4ng/ml) occurred at 0.3 ± 0.1h, post-dose. The absolute oral bioavailability of villocarine A was 16.8 ± 0.1%. To our knowledge, this was the first pharmacokinetic study of villocarine A, which demonstrated the essential pharmacokinetic properties of villocarine A: large volume distribution, high clearance, and low oral bioavailability in rats.

Pharmacokinetics of N-acetyl-l-cysteine in chickens.

N-acetyl-l-cysteine (NAC) has been suggested as an antioxidant that can alleviate the negative effects of stress conditions in broilers. However, knowledge of its pharmacokinetics (PK) in this avian species is very limited. Therefore, the study aimed to shed more light on the PK properties of NAC in chickens. Broilers were subjected to single intravenous (i.v.) or oral (p.o.) treatment or multiple NAC administrations via the feed. Drug concentrations were determined by LC-MS/MS, and the data were subjected to non-compartmental analysis and modeled by non-linear mixed effect approach. NAC was eliminated in a short time after i.v. treatment, with a t1/2el of 0.93 (0.59-2.09) h. It showed limited distribution with population mean of volumes of distribution in the central and peripheral compartments V1 of 0.148 L/kg and V2 of 0.199 L/kg, respectively, and Vdarea of 0.39 (0.258-0.635) L/kg. The value of MRT was 1.76 h (range of 0.96-2.69, p < .05) after single p.o. treatment, indicating a twofold increase if compared to i.v. administration (0.87 h, 0.55-1.78). Both methods of Pk analysis revealed very limited bioavailability, <10%. Feeding behavior led to a later achievement of lower maximum plasma concentrations (5.74, range of 3.44-9.32 μg/mL, p < .05), which were maintained during the 5 days of treatment.

Population Pharmacokinetic Modeling of Unbound Meropenem in Patients Undergoing Continuous Renal Replacement Therapy: An Observational Cohort Study.

The most effective dosing strategy of meropenem for patients undergoing continuous renal replacement therapy (CRRT) remains uncertain. This study aimed to analyze the population pharmacokinetics (popPKs) of unbound meropenem and establish an appropriate dosing approach. This prospective study involved 19 patients for the development of a popPK model and an additional 10 for its validation. Ethical approval was obtained. The clearance of unbound meropenem was influenced by the sequential organ failure assessment (SOFA) score [=2.22 × (SOFA score/12)^1.88] and the effluent flow rate from the CRRT device, with an interindividual variability of 44.5%. The volume of distribution was affected by the simplified acute physiology score II [=23.1 × (simplified acute physiology score II/52)^1.54]. Monte Carlo simulations suggested meropenem doses ranging from 1.0 to 3.0 g/d using continuous infusion to achieve a target time above the 4 times of minimum inhibitory concentration of the unbound form (%fT>4×MIC) of 100% for definitive therapy. For empirical therapy, a dose of 1.0 g/d using continuous infusion was recommended to target %fT>MIC of 100%. This study developed a popPK model for unbound meropenem in patients undergoing CRRT and formulated dosing guidelines. UMIN000024321.

Glutamate Signaling in Patients With Parkinson Disease With REM Sleep Behavior Disorder.

Clinical heterogeneity of patients with Parkinson disease (PD) is well recognized. PD with REM sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher nonmotor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning imbalances in neurotransmitter systems remain elusive. Combining magnetic resonance (MR) spectroscopy and [11C]ABP688 PET on a PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with PD. Patients were grouped according to their RBD status in overnight video-polysomnography and compared with age-matched and sex-matched healthy control (HC) participants. Total volumes of distribution (VT) of [11C]ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between 45 and 60 minutes of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single-voxel stimulated echo acquisition mode MR spectroscopy of the left basal ganglia. We measured globally elevated VT of [11C]ABP688 in 16 patients with PD and RBD compared with 17 patients without RBD and 15 HC participants (F(2,45) = 5.579, p = 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VT of [11C]ABP688. VT of [11C]ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600, p = 0.023) and with dopaminergic treatment response in patients with PD (F(1,30) = 5.823, p = 0.022). Our results suggest that patients with PD and RBD exhibit altered glutamatergic signaling indicated by higher VT of [11C]ABP688 despite unaffected glutamate levels. The imbalance of glutamate receptors and MR spectroscopy glutamate metabolite levels indicates a novel mechanism contributing to the heterogeneity of PD and warrants further investigation of drugs targeting mGluR5.

Enhancing Housing Finance for Socio-Economic Stability in Uzbekistan

Enhancing Housing Finance for Socio-Economic Stability in Uzbekistan

Mechanistic account of distinct change in organic anion transporting polypeptide 1B (OATP1B) substrate pharmacokinetics during OATP1B-mediated drug-drug interactions using physiologically-based pharmacokinetic modeling.

The role of transporters in drug clearance is widely acknowledged, directly and indirectly by facilitating tissue/enzyme exposure. Through the latter, transporters also affect volume of distribution. Drug-drug interactions (DDIs) involving organic anion transporting polypeptides (OATPs) 1B1/1B3 and SLCO1B1 pharmacogenetics lead to altered pharmacokinetics of OATP1B substrates; however, several factors may confound direct interpretation of pharmacokinetic parameters from these clinical studies using noncompartmental analysis (NCA). A review of clinical data herein indicates a single dose of OATP1B inhibitor rifampin almost never leads to increased substrate half-life but often a decrease, and that most clinical OATP1B substrates are CYP3A4 substrates and/or undergo enterohepatic cycling (EHC). Using hypothetically simple OATP1B substrate physiologically-based pharmacokinetic (PBPK) models, simulated effect of rifampin differed from specific OATP1B inhibition, due to short rifampin half-life causing dissipation of OATP1B inhibition over time combined with CYP3A4 induction. Calculated using simulated tissue data, volume of distribution indeed decreased with OATP1B inhibition and was expectedly limited to the contribution of liver volume. However, an apparent and counterintuitive effect of rifampin on volume greater than that on clearance resulted for CYP3A4 substrates, using NCA. Effect of OATP1B inhibition and rifampin on OATP1B substrate models incorporating EHC +/- renal clearance was distinct compared to simpler models. Using PBPK models incorporating reversible lactone metabolism for clinical OATP1B substrates atorvastatin and pitavastatin, DDIs reporting decreased half-life with rifampin were reproduced. These simulations provide explanation for the distinct change in OATP1B substrate pharmacokinetics observed in clinical studies, including changes in volume of distribution and additional mechanisms. Significance Statement Transporters are involved in both drug clearance and volume of distribution and distinct changes in OATP1B substrate pharmacokinetics are observed with OATP1B inhibitor rifampin. Using hypothetical and validated PBPK models and simulations we address the limitations of single-dose rifampin and complicated clinical OATP1B substrate disposition in evaluating the pharmacokinetic parameters of OATP1B substrates during rifampin DDIs. These models account for the change in volume of distribution and identify additional mechanisms underlying apparent pharmacokinetic changes in OATP1B DDIs.

Pooled Population Pharmacokinetic Analysis and Dose Recommendations for Ciprofloxacin in Intensive Care Unit Patients with Obesity.

Recent studies have explored the influence of obesity and critical illness on ciprofloxacin pharmacokinetics. However, variation across the subpopulation of individuals with obesity admitted to the intensive care unit (ICU) with varying renal function remains unexamined. This study aims to characterize ciprofloxacin pharmacokinetics in ICU patients with obesity and provide dose recommendations for this special population. Individual patient data of 34 ICU patients with obesity (BMI >30 kg/m2) from four studies evaluating ciprofloxacin pharmacokinetics in ICU patients were pooled and combined with data from a study involving 10 individuals with obesity undergoing bariatric surgery. All samples were collected after intravenous administration. Non-linear mixed effects modeling and simulation were used to develop a population pharmacokinetic model and describe ciprofloxacin exposure in plasma. Model-based dose evaluations were performed using a pharmacokinetic/pharmacodynamic target of AUC/MIC >125. The data from patients with BMI ranging from 30.2 to 58.1 were best described by a two-compartment model with first-order elimination and a proportional error model. The inclusion of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as a covariate on clearance reduced inter-individual variability from 57.3% to 38.5% (P <.001). Neither body weight nor ICU admission significantly influenced clearance or volume of distribution. Renal function is a viable predictor for ciprofloxacin clearance in ICU patients with obesity, while critical illness and body weight do not significantly alter clearance. As such, body weight and critical illness do not need to be accounted for when dosing ciprofloxacin in ICU patients with obesity. Individuals with CKD-EPI >60 mL/min/1.73 m2 may require higher dosages for the treatment of pathogens with minimal inhibitory concentration ≥0.25 mg/L.

Kinetic modeling of the monoamine oxidase-B radioligand [18F]SMBT-1 in human brain with positron emission tomography.

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [18F](S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression. Fourteen elderly subjects (8 control, 5 mild cognitive impairment, 1 Alzheimer's disease) with amyloid ([11C]PiB) and tau ([18F]flortaucipir) imaging assessments underwent dynamic [18F]SMBT-1 PET imaging with arterial input function determination. [18F]SMBT-1 showed high brain uptake and a retention pattern consistent with the known MAO-B distribution. A two-tissue compartment (2TC) model where the K1/k2 ratio was fixed to a whole brain value best described [18F]SMBT-1 kinetics. The 2TC total volume of distribution (VT) was well identified and highly correlated (r2∼0.8) with post-mortem MAO-B indices. Cerebellar grey matter (CGM) showed the lowest mean VT of any region and is considered the optimal pseudo-reference region. Simplified analysis methods including reference tissue models, non-compartmental models, and standard uptake value ratios (SUVR) agreed with 2TC outcomes (r2 > 0.9) but with varying bias. We found the CGM-normalized 70-90 min SUVR to be highly correlated (r2 = 0.93) with the 2TC distribution volume ratio (DVR) with acceptable bias (∼10%), representing a practical alternative for [18F]SMBT-1 analyses.

Dynamic edge clustering and task scheduling for edge assisted metaverse system in the field of remote work and collaboration

SummaryThe metaverse, a future digital world for living, working, learning, and interacting, is rapidly gaining significance, particularly in the domain of remote work and collaboration. This emerging digital landscape demands high‐performance, low‐latency, and scalable services to provide an immersive user experience. The current technology used in metaverse systems has some limitations, which emphasize the importance of adopting emerging technologies like Edge Computing (EC). However, as the number of users and data volume increases, it can impact both system performance and scalability of the edge‐assisted metaverse system. Additionally, the uneven distribution of edge servers can cause inconsistencies and result in high latency. To overcome these challenges, this paper proposes a dynamic edge clustering and task scheduling approach for edge‐assisted metaverse systems (DTAM) in the field of remote work and collaboration. The proposed approach addresses the challenges of high user volume and uneven resource distribution by incorporating dynamic clustering and edge server assistance to improve clustering performance. Furthermore, a Prioritized Experience Replay‐based Deep Q‐learning algorithm with state augmentation (PERDQSA) for task scheduling is introduced to improve sample efficiency and performance. The performance of the proposed DTAM is evaluated against existing techniques, and experimental results demonstrate its significant superiority in terms of specific metrics such as bandwidth, task response time, energy efficiency, and latency. The experiments demonstrated that DTAM outperforms Transformation‐based Edge Computing Deep Q‐Learning (TransEC‐DQL) in several key metrics. Specifically, DTAM achieves 28.5% reduction in latency, 13.7% reduction in response time, and 6.4% improvement in bandwidth compared to TransEC‐DQL. These results signify that DTAM can deliver a significantly enhanced user experience in the metaverse, particularly in the context of remote work and collaboration.

Studies of Fractal Microstructure in Nanocarbon Polymer Composites.

The in situ study of fractal microstructure in nanocarbon polymers is an actual task for their application and for the improvement in their functional properties. This article presents a visualization of the bulk structural features of the composites using pulsed acoustic microscopy and synchrotron X-ray microtomography. This article presents details of fractal structure formation using carbon particles of different sizes and shapes-exfoliated graphite, carbon platelets and nanotubes. Individual structural elements of the composite, i.e., conglomerations of the particles in the air capsule as well as their distribution in the composite volume, were observed at the micro- and nanoscale. We have considered the influence of particle architecture on the fractal formation and elastic properties of the composite. Acoustic and X-ray imaging results were compared to validate the carbon agglomeration.

Pharmacokinetics of tildipirosin in estuarine (Crocodylus porosus) and freshwater (Crocodylus siamensis) crocodiles

Tildipirosin is a macrolide antimicrobial. It is authorised for the treatment and prevention of respiratory disease in cattle and pigs. There are no data on its administration in crocodiles. Therefore, this study evaluated the disposition kinetics of tildipirosin after intravenous (dose: 2 mg/kg) and intramuscular (doses: 2 and 4 mg/kg) administration in two crocodilian species (estuarine and freshwater; n = 5). Tildipirosin plasma concentrations were quantified by a validated HPLC method. Plasma concentrations obtained at each extraction time were analysed by non-compartmental methods. In the estuarine and freshwater crocodiles, the apparent volumes of distribution of tildipirosin after intravenous administration were 0.36 ± 0.10 and 1.48 ± 0.26 L/kg, respectively. These values, suggesting poorer tissue distribution, were much lower than those obtained in mammals. There was complete bioavailability of tildipirosin after intramuscular route at a dose of 2 mg/kg; however, at a dose of 4 mg/kg the bioavailability decreased by about 20–25 %. Furthermore, the pharmacokinetics of tildipirosin were markedly different in the two crocodilian species. Considering a MIC of 0.5 µg/mL, the surrogate marker AUC0–24/MIC indicates that tildipirosin would greatly exceed the value of 65 h for both crocodile species and dose levels tested. This suggests that both doses (2 and 4 mg/kg) may provide a bactericidal effect. Therefore, based on the absence of adverse reactions following the administration of tildipirosin in both crocodilian species, and considering its favourable pharmacokinetic properties, tildipirosin may be useful in treating infections in these reptiles.

How government policies promote transportation utilization in the national-level hydrogen supply chain: A case of China

Pipeline transportation is a low-cost option for delivering large volumes of hydrogen (H2), however, the high initial capital cost remains a major impediment to expanding pipeline delivery infrastructure. To quantitatively evaluate the impact of the H2 pipeline on the hydrogen supply chain (HSC), this paper develops an evaluation system for the development potential of the H2 pipeline and simulation models for H2 resource allocation. Furthermore, the HSC system in the southwest of China is used to validate the proposed method. The results demonstrate that the levelized cost range of a given 150–550 km H2 pipeline is 2.76–10.12 CNY/kg, which has price advantages over other transportation modes. Compared with the hydrogen supply chain resource allocation (HSCR) model, putting the H2 pipeline into use can optimize the layout and utilization of different transportation modes. It shows that the proportion of H2 transportation volume distribution in H2 pipelines has increased from 0 % to 73.44 %, while the proportion of HLT has first increased from 18.86 % to 54.27 %, and then decreased to 17.95 %. And then under different policy scenarios, the consideration of pipeline reduces the sensitivity of the H2 blending ratio of natural gas (NG) and NG demand to HSC. The impacts of policies on regional H2 development and regional policy implications are revealed. This approach provides a tool for policymakers to quantify the impacts of policy.

Assessment of body mass-related covariates for rifampicin pharmacokinetics in healthy Caucasian volunteers.

Currently, body weight-based dosing of rifampicin is recommended. But lately, fat-free mass (FFM) was reported to be superior to body weight (BW). The present evaluation aimed to assess the influence of body mass-related covariates on rifampicin's pharmacokinetics (PK) parameters in more detail using non-linear mixed effects modeling (NLMEM). Twenty-four healthy Caucasian volunteers were enrolled in a bioequivalence study, each receiving a test and a reference tablet of 600mg of rifampicin separated by a wash-out period of at least 9days. Monolix version 2023R1 was used for NLMEM. Monte Carlo simulations (MCS) were performed to visualize the relationship of body size descriptors to the exposure to rifampicin. A one-compartment model with nonlinear (Michaelis-Menten) elimination and zero-order absorption kinetics with a lag time best described the data. The covariate model including fat-free mass (FFM) on volume of distribution (V/F) and on maximum elimination rate (Vmax/F) lowered the objective function value (OFV) by 56.4. The second-best covariate model of sex on V/F and Vmax/F and BW on V/F reduced the OFV by 51.2. The decrease in unexplained inter-individual variability on Vmax/F in both covariate models was similar. For a given dose, MCS showed lower exposure to rifampicin with higher FFM and accordingly in males compared to females with the same BW and body height. Our results indicate that beyond BW, body composition as reflected by FFM could also be relevant for optimized dosing of rifampicin. This assumption needs to be studied further in patients treated with rifampicin.