Volume Of Distribution Research Articles

Predicting Human Subcutaneous Bioavailability of Therapeutic Monoclonal Antibodies from Systemic Clearance and Volume of Distribution.

Subcutaneous delivery of monoclonal antibody therapeutics is often preferred to intravenous delivery due to better patient compliance and overall lower cost to the healthcare system. However, the systemic absorption of biologics dosed subcutaneously is often incomplete. The aim of this work was to describe a human bioavailability prediction method for monoclonal antibodies delivered subcutaneously that utilizes intravenous pharmacokinetic parameters as input. A two-compartment pharmacokinetic model featuring a parallel-competitive absorption pathway and a presystemic metabolism pathway was employed. A training data set comprised 19 monoclonal antibodies (geometric mean bioavailability of 68%), with previously reported human pharmacokinetic parameters, while a validation set included data compiled from 5 commercial drug products (geometric mean bioavailability of 69%). A single fitted absorption rate constant, paired with compound-specific estimates of presystemic metabolism rate proportional to compound-specific systemic clearance parameters, resulted in calculations of human subcutaneous bioavailability closely mimicking clinical data in the training data set with a root-mean-square error of 5.5%. Application of the same approach to the validation data set resulted in predictions characterized by 12.6% root-mean-square error. Factors that may have impacted the prediction accuracy include a limited number of validation data set compounds and an uncertainty in the absorption rate, which were subsequently discussed. The predictive method described herein provides an initial estimate of the subcutaneous bioavailability based exclusively on pharmacokinetic parameters available from intravenous dosing.

Determination of Demand for LNG in Poland

This study was aimed at improving the energy efficiency of the distribution of liquefied natural gas (LNG) as shipping fuel in the southern Baltic Sea. The objective of this study was to determine the demand for LNG for maritime shipping by analyzing the distribution of the resource from the water side (ship-to-ship). LNG was chosen due to the location of the LNG terminal in Świnoujście within the analyzed water area, where a problem has arisen in the southern part of the Baltic Sea regarding fuel supply for vessels due to the lack of developed infrastructure along the coast. An analysis was conducted to optimize the size of the LNG fleet and infrastructure facilities. Seeking compliance with Annex VI to the MARPOL 73/78 Convention, adopted by the International Maritime Organization (IMO), shipowners see potential in the switch from conventional fuels to LNG. As one of the alternative solutions, it will contribute to reducing harmful emissions. Determination of the LNG distribution volume requires the identification of LNG storage facility locations, specifying the number of LNG-powered ships (broken down by type) and the number of LNG bunkering ships. The first part of this study contains a detailed analysis of the number of sea-going ships that provide services in the southern part of the Baltic Sea and the world’s number of LNG bunkering ships. The database contains a set of the characteristics required to determine the optimal demand for LNG, where LNG bunkering vessels are capable of supplying fuel within the shortest possible time and covering the shortest possible distance to LNG-powered ships. The characteristics include the type of ship, requested LNG volume, the speed of LNG bunkering ships, the distance between LNG facilities, and the loading rate (the volume of fuel received per time unit). Based on the collected data, the volume of LNG distribution was determined using MATLAB R2019a software. The remainder of this study contains a description of the conducted research and results of an analysis of the traffic density in the Baltic Sea. The results were obtained on the basis of data from the Statistical Yearbook of Maritime Economy and IALA IWRAP Mk2 2020 software. The number of LNG-powered ships and number of LNG bunkering ships were specified, and the demand for LNG for the area under analysis was determined.

Comparing PEMFC state-of-health characteristics obtained by Galvanostatic Charge Method with and without nitrogen flush

Onboard determination of state-of-health (SoH) parameters becomes increasingly important with tightened lifetime requirements for automotive polymer electrolyte membrane (PEM) fuel cell systems. One way to electrochemically characterize SoH parameters like active catalyst surface area (roughness factor, RF), double layer capacitance and membrane permeability is the nitrogen-flush-requiring Galvanostatic Charge Method (GCM). In this publication, a nitrogen-flush-free and thus, onboard-compatible adapted version of GCM (AGCM from Möller et al. (2023)), is directly compared to its original method, GCM. A 20-cell automotive shortstack was frequently characterized with both GCM and AGCM methods as well as standard Cyclic Voltammetry (CV) during a degradation test. Additionally, the evaluation model for AGCM was varied in two aspects: Firstly, modeling the hydrogen partial pressure difference (ΔpH2) responsible for hydrogen crossover and secondly, modeling hydrogen diffusion in the cathode volume with a 0-D transport model. The characterization results prove that all investigated model variations of AGCM can reproduce double layer capacitance results from GCM and CV, as well as the decreasing trend in roughness factor results. RF-values characterized by AGCM agree with either GCM or CV results, depending on the evaluation model. A thorough analysis revealed the neglected short circuit resistance in combination with the chosen modeling approach of ΔpH2 in AGCM as the reason. The two modeling approaches for ΔpH2 base on extreme assumptions about the homogeneity of hydrogen distribution in the anode volume. Neither of them could reproduce the membrane permeability of GCM. Instead, one overestimates, one underestimates it, indicating the truth to be in between the two extreme models. However, AGCM measurement conditions are identified as a lever to improve the AGCM permeability results and their robustness, even if the modeling approaches remain unchanged. Furthermore, this study showed that neglecting hydrogen diffusion in the cathode volume in the AGCM evaluation model leads to overestimation of the membrane permeability.

Assessing masseter muscle volume and activity in relation to craniofacial morphology: a 3D CBCT study.

Understanding the factors influencing craniofacial structure growth is crucial for addressing craniofacial deformities. This study evaluates masseter muscle volume, activity, and maximum bite force across different skeletal malocclusion groups and aims to evaluate the masseter muscle volume, activity, and maximum bite force (BF) according to different skeletal malocclusion groups. This study aimed to assess masseter muscle volume, activity, and maximum bite force (BF) across different skeletal malocclusion groups in 60 young adults (18-30 years) seeking treatment at Kirikkale University Faculty of Dentistry. Cone-Beam Computed Tomography (CBCT) imaging, radiological measurements, surface electromyography (sEMG), and force sensor measurements were employed. Results revealed significant differences in sEMG measurements based on sagittal classification. Vertical direction groups showed notable results in muscle volume and BF, though no significant differences were observed in sEMG values. A correlation was identified between BF and sEMG, but no correlation was found between muscle volume and other parameters. The findings obtained in this study suggest that the significant relationship between EMG and sagittal skeletal classification could be a valuable diagnostic tool. However, concerns about reliability were raised due to uneven distribution in muscle volume and BF among vertical direction groups. The lack of significant results in muscle volume, sEMG, and BF was attributed to CBCT limitations in soft tissue imaging and the small sample size, emphasizing caution in interpreting the findings.

EXO: A commons-based community network Internet Service Provider, description and subscribers usage patterns

The advent of Wi-Fi in the 1990s stimulated the creation of Community networks (CNs), a new networking paradigm deployed and maintained by their users. The non-profit and grassroots self-organization of CNs has shown significant potential in enhancing communication technologies grounded in ethical values, transcending mere Internet expansion to contribute to broader social impacts. Since its conception, hundreds of CNs have been deployed worldwide. However, many have faltered, primarily due to a lack of solid economic models and legal setup. This paper presents Expansió Xarxa Oberta (eXO) association, a commons Internet Service Provider (ISP). In contrast to commercial ISPs, eXO follows the same grassroots principles of CNs. Establishing a commons-based ISP is challenging, yet it is a key component for the sustainability and success of CNs. Therefore, our paper aims to dissect the complexity of a commons ISP by explaining eXO, a pioneering example that has already been in production for more than 14 years. To the best of our knowledge, this is the first time that a commons ISP is described in all its components.To describe eXO, we have proceeded in two parts. In the first one, we delineate the organizational structure, economics, funding mechanisms, activities, legal framework, and infrastructure. To gain more insight on eXO, in the second part, we conduct a technical analysis of traffic data collected from eXO’s core router, elucidating subscriber usage patterns. Our study encompasses various subscriber categories, including regular and financially subsidized users, Wi-Fi and optical fiber access, and traffic characteristics such as volume, TCP/UDP usage, services accessed, and traffic distribution across countries.

A steady-state distributed parameter ultrathin heat pipe model considering the unsaturated wick

Ultrathin heat pipes have become mainstream to address the heat dissipation issues of small electronic devices. Numerous numerical studies based on the saturated wick assumption have been proposed to analyze their heat transfer performance. In order to achieve a more accurate assessment, this study presents a three-dimensional model that quantitatively reflects the relationship between capillary pressure and medium volume, along with a corresponding correlation. Based on this, a steady-state distributed parameter ultrathin heat pipe model considering the retreating of medium volume in the wick and the unsaturation vapor-liquid interface was developed, whose accuracy was verified by the experimental data. The results demonstrated that the capillary pressure increased with the decrease of medium volume and contact angle. The evolution of the overall meniscus with medium volume was categorized into two stages, where capillary pressure dependent on the main and micro meniscus at different stage. The medium volume distribution, corresponding to capillary pressure, will automatically adjust to match the overall medium pressure drop. Comparative analysis against experimental data, the proposed model reduced the maximum temperature difference error by 8.43 % compared to the saturated wick assumption at a heat load of 6 W, revealing that the unsaturated liquid wick model exhibited higher accuracy.

Advances in CT-based lung function imaging for thoracic radiotherapy.

The objective of this review is to examine the potential benefits and challenges of CT-based lung function imaging in radiotherapy over recent decades. This includes reviewing background information, defining related concepts, classifying and reviewing existing studies, and proposing directions for further investigation. The lung function imaging techniques reviewed herein encompass CT-based methods, specifically utilizing phase-resolved four-dimensional CT (4D-CT) or end-inspiratory and end-expiratory CT scans, to delineate distinct functional regions within the lungs. These methods extract crucial functional parameters, including lung volume and ventilation distribution, pivotal for assessing and characterizing the functional capacity of the lungs. CT-based lung ventilation imaging offers numerous advantages, notably in the realm of thoracic radiotherapy. By utilizing routine CT scans, additional radiation exposure and financial burdens on patients can be avoided. This imaging technique also enables the identification of different functional areas of the lung, which is crucial for minimizing radiation exposure to healthy lung tissue and predicting and detecting lung injury during treatment. In conclusion, CT-based lung function imaging holds significant promise for improving the effectiveness and safety of thoracic radiotherapy. Nevertheless, challenges persist, necessitating further research to address limitations and optimize clinical utilization. Overall, this review highlights the importance of CT-based lung function imaging as a valuable tool in radiotherapy planning and lung injury monitoring.

Development and validation of an LC-MS/MS method for the quantification of free and total doxorubicin in human plasma and its clinical application for a novel doxorubicin hydrochloride liposome injection in Chinese patients with breast cancer

AbstractA novel doxorubicin hydrochloride liposome injection was prepared to reduce toxicity and side effects, as well as extend plasma half-life in the treatment of breast cancer. In this study, a rapid and sensitive bioanalytical method was developed and validated to characterize the pharmacokinetic profile of total and free doxorubicin in plasma of 3 Chinese patients after intravenous infusion of this injection. Plasma samples were prepared by protein precipitation for the determination of total doxorubicin, while solid phase extraction was used to determine free doxorubicin. After plasma sample pre-treatment, total and free concentrations were quantified individually using a validated LC-MS/MS method. The calibration curves were found to be linear in the range of 0.20–500.0 ng mL−1 for total doxorubicin and in the range of 1.00–1,000 ng mL−1 for free doxorubicin. The free concentrations in plasma were only one sixth to one quarter of the total levels. Liposomal doxorubicin had a longer apparent half-life (>50 h) than the non-targeted drug (<10 h) reported in the reference. and a lower volume of distribution. This novel injectable formulation steadily released free doxorubicin from liposomes over a long period of time to reduce cardiac toxicity and side effects, while ensuring a clinical curative effect.

Documento nacional de consenso de monitorización terapéutica de antibióticos y antifúngicos en el paciente pediátrico y neonatal de la Sociedad Española de Farmacia Hospitalaria (SEFH) y la Sociedad Española de Infectología Pediátrica (SEIP)

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic param- eters, is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised host.In neonates and children, infections account for a high percentage of hospital admissions and anti-infectives are the most used drugs. However, pediatric pharmacokinetic and pharmacodynamic studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals -usually used off-label in pediatrics- to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the pharmacokinetic parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treat- ment success. In addition, pediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.The aim of this document, developed jointly between the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Pediatric Infectious Diseases (SEIP), is to describe the available evidence on the indications for therapeutic drug monitoring of antibiotics and antifungals in newborn and pediatric patients and to provide prac- tical recommendations for therapeutic drug monitoring in routine clinical practice to optimize pharmacokinetic and pharmacodynamic parameters, efficacy and safety of antibiotics and antifungals in the pediatric population.

Pharmacokinetics of methadone after intravenous and subcutaneous administration in domestic ferrets (Mustela putorius furo)

ObjectiveTo determine the pharmacokinetic profile of methadone after intravenous (IV) and subcutaneous (SC) administration in domestic ferrets (Mustela putorius furo). Study designCrossover experimental study. AnimalsA group of eight healthy adult ferrets weighing 1.01 ± 0.23 kg [mean ± standard deviation (SD)]. MethodsMethadone hydrochloride (0.3 mg kg-1) was injected IV or SC to each ferret with a 3 week washout period. Blood samples were collected via a jugular catheter before and 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 360, and 480 minutes following drug administration. Liquid chromatography-tandem mass spectrometry was used to determine plasma methadone concentrations. A nonlinear mixed effects model was used to analyze the data. ResultsFollowing IV injection, systemic clearance (Clss) and volume of distribution (Vdss) were 78.9 mL min-1 kg-1 and 9.8 L kg-1, respectively. Elimination half-life was 2.0 hours and SC bioavailability was fixed at 1. The maximum observed plasma concentration after SC injection was 92.1 ± 76.8 ng mL-1. Behavioral changes were observed after both routes. Conclusions and clinical relevanceThe pharmacokinetic profile of IV methadone was characterized by a high Clss and large Vdss, with high bioavailability and absorption rate following SC administration. Half-life was short and mean plasma methadone concentrations stayed above the minimum effective concentration (MEC) reported in humans only after SC administration for 5 minutes, but remained above that reported in dogs for 45 minutes following both routes. Further studies investigating the MEC and pharmacodynamics of methadone in ferrets are warranted.

Documento nacional de consenso de monitorización terapéutica de antibióticos y antifúngicos en el paciente pediátrico y neonatal de la Sociedad Española de Farmacia Hospitalaria (SEFH) y la Sociedad Española de Infectología Pediátrica (SEIP)

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic parameters, is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised host.In neonates and children, infections account for a high percentage of hospital admissions and anti-infectives are the most used drugs. However, pediatric pharmacokinetic and pharmacodynamic studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals -usually used off-label in pediatrics- to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the pharmacokinetic parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, pediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.The aim of this document, developed jointly between the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Pediatric Infectious Diseases (SEIP), is to describe the available evidence on the indications for therapeutic drug monitoring of antibiotics and antifungals in newborn and pediatric patients and to provide practical recommendations for therapeutic drug monitoring in routine clinical practice to optimize pharmacokinetic and pharmacodynamic parameters, efficacy and safety of antibiotics and antifungals in the pediatric population.

[Translated article] Therapeutic Drug Monitoring of antibiotic and antifungical drugs in paediatric and newborn patients. Consensus Guidelines of the Spanish Society of Hospital Pharmacy (SEFH) and the Spanish Society of Paediatric Infectious Diseases (SEIP)

Therapeutic monitoring of antibiotics and antifungals based on pharmacokinetic and pharmacodynamic (PK/PD) parameters is a strategy increasingly used for the optimization of therapy to improve efficacy, reduce the occurrence of toxicities, and prevent the selection of antimicrobial resistance, particularly in vulnerable patients including neonates and the critical or immunocompromised paediatric host.In neonates and children, infections account for a high percentage of hospital admissions, and anti-infectives are the most used drugs. However, paediatric PK/PD studies and the evidence regarding the efficacy and safety of some newly marketed antibiotics and antifungals—usually used off-label in paediatrics—to determine the optimal drug dosage regimens are limited. It is widely known that this population presents important differences in the PK parameters (especially in drug clearance and volume of distribution) in comparison with adults that may alter antimicrobial exposure and, therefore, compromise treatment success. In addition, paediatric patients are more susceptible to potential adverse drug effects and they need closer monitoring.The aim of this document, developed jointly by the Spanish Society of Hospital Pharmacy and the Spanish Society of Paediatric Infectious Diseases, is to describe the available evidence on the indications for therapeutic drug monitoring (TDM) of antibiotics and antifungals in newborn and paediatric patients, and to provide practical recommendations for TDM in routine clinical practice to optimise their dosing, efficacy and safety. Of antibiotics and antifungals in the paediatric population.

A pilot pharmacokinetic and Metabolite identification study of Erinacine A in a Single landrace pig model

Erinacine A has been proven to have the ability to protect nerves and have the benefit of neurohealth. However, the pharmacokinetic and metabolites study of erinacine A in pigs, whose physiology and anatomy are similar to humans, have not been reported. In this study, 5 mg/kg of erinacine A was intravenously administered to the landrace pig. Blood, cerebrospinal fluid, and brain tissue samples were collected and analyzed by HPLC-QQQ/MS and UPLC-QTOF/MS. The results indicated the following pharmacokinetic parameters in plasma samples: with an area under the plasma concentration versus time curve (AUC) were 38.02 ± 0.03 mg∙min/L (AUC0-60) and 43.60 ± 0.06 mg∙min/L (AUC0-∞), clearance (CL) was 0.11 ± 0.00 L/min∙kg, volume of distribution (Vd) was 4.24 ± 0.00 L/kg, and terminal half-life (T1/2β) was 20.85 ± 0.03 min. In the cerebrospinal fluid samples, erinacine A was detected after 15 min and the highest concentration (5.26 ± 0.58 μg/L) was observed at 30 min. In the brain tissue sample, 77.45 ± 0.58 μg/L of erinacine A was found. In the study of metabolites, there were 6 identical metabolites in plasma and brain tissue. To our surprise, erinacine B was found to be the metabolite of erinacine A, and its concentration increased over time as erinacine A was metabolized. In summary, this study is the first to demonstrate that erinacine A can be found in the cerebrospinal fluid of landrace pigs. Additionally, the metabolite identification of erinacine A in landrace pigs is also investigated.

Novel single-cell measurements suggest irreversibly sickled cells are neither dense nor dehydrated

In sickle cell anemia, deoxygenation causes erythrocytes to distort, while reoxygenation permits them to recover a normal biconcave disk shape. Irreversibly sickled cells (ISCs) remain distorted when reoxygenated and have been thought to have among the highest intracellular hemoglobin concentrations of the sickle red cell population and therefore the greatest vulnerability to vasoocclusion. Using a new optical method, which we describe, we have made precise measurements of the intracellular hemoglobin concentration, and intracellular O2 saturation, of ISCs, as well as oxygenated sickle cells with a normal biconcave disc shape, and cells with shapes distorted by the sickle fibers they contain. This method also provides good estimates of cell volumes, and hemoglobin per red cell. The concentration distribution of the ISCs is found to be similar to normal, discoid cells. Average ISC volumes exceed their discoid counterparts, with a much broader distribution, arguing against dehydration as their origin. The concentration distribution of the polymer-laden sickled cells is significantly higher in mean value, and their volume distributions indicate some dehydration. Previous assumptions about ISCs may have thus been colored by the presence of sickle cells that did contain polymer, and that true ISCs may be much more benign than once thought, which underscores the importance of accurate measurement on individual cells. This method could be used to follow changes in individual cell properties under various specific perturbations, and where characterization by flow cytometry is infeasible.

O21 PLATELET COUNT-TO-PLATELET DISTRIBUTION WIDTH RATIO AND OTHER PLATELET INDICES AS COST-EFFECTIVE MARKERS OF PREECLAMPSIA: A CASE CONTROL STUDY

Background and objective: Platelet indices, like platelet count (PC), plateletcrit, mean platelet volume (MPV) and platelet distribution width (PDW), and their ratios have shown to be cost-effective and better predictors of preeclampsia (PE). However, PC/PDW ratio was not studied. Thus, this study aimed to compare platelet indices and their ratios between pregnant women with and without PE. Methods: An analytical, comparative, case-control study. Two groups were compared; pregnant women with PE (case, n=24) and without PE (control, n=72). The differences between cases and controls were compared using Student's t-test and Mann–Whitney U-test for continuous variables and chi-square tests and Fisher's exact test for categorical. Multivariable linear regression analysis for hematological parameters was performed to assess the effect of gestational age. Logistic regression was performed to calculate the odds ratio. Receiver operating characteristic curve was used to determine sensitivity, specificity and cutoff values. P < 0.05 was considered significant. Results: There was significant reduction in values of PC (p=0.004), plateletcrit (p=0.012), PC/MPV ratio (p=0.002), and PC/PDW (p= <0.001) among the pregnant women with PE compared to the control study group, while a significant increase was noticed in the values of PDW (p= <0.001) and MPV (p=0.021). PC/PDW had the highest area under the curve (AUC) of 0.767, followed by PDW (AUC=0.752). At the cutoff value of 15.1 (p<0.001) for PC/PDW, sensitivity was 70.8%, and specificity was 81.9%. The odds of diagnosing true positive cases of PE was 11.02 (95% CI =3.79-31.99, p=<0.001) times higher compared to values below it at this cutoff point. Conclusions: Present study suggests that platelet indices are economical tests that can act as indicators of risk of PE. Among all the parameters, PC/PDW has the highest sensitivity and specificity in the detection of PE at the cutoff of 15.1 and has emerged as a better predictor of PE.

Quantitative analysis of peripapillary capillary volume using dense B-scan OCT angiography in normal and diabetic retina

BackgroundThe value of quantitatively analyzing peripapillary capillary volume (PPCV) distribution was explored in normal and diabetic retinopathy (DR) eyes using dense B-scan optical coherence tomography angiography (DB OCTA).MethodsThis was a cross-sectional observational study followed by prospective follow-up for those with DR, which enrolled 101 healthy subjects and 140 DR patients. Dense, automatic, real-time (DART) volume scans of DB OCTA were performed using a Spectralis HRA + OCT2. ImageJ and MATLAB were used to process and calculate PPCV distribution detected by DB OCTA.ResultsIn normal subjects, PPCV distribution were significantly correlated with the age and quadrant location (all P < 0.001). The PPCV distribution in each quadrant was significantly lower in severe nonproliferative DR patients than in normal subjects in all age groups (all P < 0.05, t-test). Compared to normal subjects, the PPCV distribution improved significantly in the pan-retinal photocoagulation treatment and surgery groups (all P < 0.001). No significant variation was observed in the anti-VEGF treatment group and normal subjects (P > 0.05). The PPCV distribution is significantly correlated with post-treatment best-corrected visual acuity in both the pan-retinal photocoagulation treatment and surgery groups (all P < 0.003) but not in the anti-VEGF treatment group (P = 0.940).ConclusionsQuantitative assessment of PPCV distribution using DB OCTA is valuable in prognosis evaluation of DR with pan-retinal photocoagulation and surgery.

Evaluation of in vivo pharmacokinetic study of the anti-cancer drug imatinib using silkworms as an animal model.

Imatinib is an oral molecular targeted therapy that acts as a tyrosine kinase inhibitor. Silkworms present a promising experimental model for elucidating the pharmacokinetic and toxicity profiles of various compounds. This study aimed to establish an experimental paradigm for investigating the pharmacokinetics of imatinib in silkworms. A comparative analysis of imatinib pharmacokinetic parameters across silkworms, humans, mice, and rats revealed similarities in time to maximum concentration (Tmax) and apparent clearance values between silkworms and humans. However, differences in elimination half-life (t1/2) and apparent volume of distribution between silkworms and humans remained within 5- and 4-fold ranges, respectively. Importantly, mice demonstrated pharmacokinetic parameters closer to those of humans than rats during imatinib studies. Additionally, silkworms and mice exhibit similar Tmax and t1/2 values. This study highlights the potential of silkworms as valuable tools for investigating imatinib metabolism in pharmacokinetic studies. Furthermore, it underscores the applicability of silkworms in elucidating the pharmacokinetic parameters of various molecular-targeted drugs, thus facilitating advancements in drug development and evaluation.

Pharmacokinetic Pattern of Menbutone in Calves after Single Intravenous and Intramuscular Administration.

Menbutone is a choleretic agent currently used in Europe to treat digestive disorders in livestock and dogs. Pharmacokinetic parameters were established in 4-month Holstein calves after intravenous (IV) and intramuscular (IM) administration. The drug was administered to 12 animals (10 mg/kg) for both IV and IM routes following a crossover design. Plasma samples were collected at various time points over 24 h and analyzed by reverse-phase high-performance liquid chromatography with a photodiode-array detector, following a method validated according to European Medicines Agency guidelines. Pharmacokinetic parameters were calculated using compartmental and non-compartmental methods. Menbutone followed a two-compartment open model after IV injection, with a total clearance (Cl) of 71.9 ± 13.5 mL/h/kg, an elimination half-life (t½β) of 4.53 ± 2.45 h, and a volume of distribution at steady-state (Vss) of 310.4 ± 106.4 mL/kg. Non-compartmental elimination half-life (t½λ) was 4.2 ± 1.1 h. After IM administration, drug pharmacokinetics was best described by a one-compartment open model. The peak plasma concentration (Cmax) was 15.1 ± 4.3 µg/mL; the time to reach Cmax (tmax), 1.66 ± 0.55 h; and the mean absorption time (MAT), 2.50 ± 1.42 h. Absorption was high, with a fraction of the dose absorbed (F) of 83.5 ± 22.4%. Menbutone was rapidly eliminated from plasma for both routes of administration, with a fast and high IM bioavailability.

Kappa opioid receptor availability predicts severity of anhedonia in schizophrenia.

The kappa opioid receptor (KOR) and its endogenous agonist dynorphin have been implicated in multiple psychiatric conditions including psychotic disorders. We tested the hypotheses that kappa expression is elevated and associated with psychotic symptoms in schizophrenia. We measured kappa expression in unmedicated patients with schizophrenia (7 female, 6 male) and matched controls (7 female, 6 male) with positron emission tomography (PET). We also acquired a measurement of cumulative dopamine activity over the life span in the same subjects using neuromelanin sensitive MRI. We hypothesized that neuromelanin accumulation would be higher in patients than controls and that in patients there would be a positive association between KOR availability and neuromelanin accumulation. Fourteen patients and thirteen controls were enrolled. Whole brain dynamic PET imaging data using the KOR selective tracer [18F]LY245998 were acquired. Distribution volume (VT) was measured with region of interest analysis in 14 brain regions. Neuromelanin accumulation in midbrain dopaminergic nuclei was assessed in the same subjects. Positive and negative symptoms were measured by a clinical psychologist. We did not observe group level differences in KOR expression, neuromelanin accumulation or relationships of these to positive symptoms. Unexpectedly, we did observe strong positive associations between KOR expression and symptoms of anhedonia in the patients (Pearson r > 0.7, uncorrected p < 0.01 in 8 cortical brain regions). We also observed moderate associations between KOR expression and neuromelanin levels in patients. In conclusion, we did not observe a relationship between kappa and symptoms of psychosis but the observed relationship to the negative symptom of anhedonia is in line with recent work testing kappa antagonism as a therapy for anhedonia in depression.

Analysis of Inherent Frequencies to Mitigate Liquid Sloshing in Overhead Double-Baffle Damper

A disco-rectangular volume-fraction-of-fluid (VOF) model tank of a prismatic size is considered here for investigating the severe effect of overhead baffles made of three different materials, nylon, polyamide, and polylactic acid. In this work, the overdamped, undamped, and nominal damped motion of baffles and their effect are studied. In this research, the behaviour of different material baffles based on the sloshing effect and natural frequency of each baffle excited in damped, undamped, and overdamped cases is studied. VOF modelling is carried out in moving Yeoh model mesh with fluid–structure interaction between the water models for various baffle plates. The results of the water volume distribution and baffle displacement operating between a sloshing time of 0 and 1 s are recorded. Also, a strong investigation is carried out for the water volume suspended on overhead baffles by three different material selections.