Volume Of Distribution Research Articles

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.

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 > 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.

Age and Sex Related Differences in Human α4β2* Nicotinic Acetylcholine Receptor Binding Evaluated with [18F]Nifene PET

Abstract Neuronal α4β2* nicotinic acetylcholine receptors (nAChRs) are stimulated by nicotine and are associated with tobacco dependence. [18F]Nifene is a PET radiotracer with high specificity for α4β2* nAChRs that can be used to investigate nAChR distribution in the human brain in vivo. In this study we investigate the dependence of sex and age on the binding of [18F]nifene in nonsmoking healthy human participants. Cognitively normal participants (n = 31) were recruited into older vs. younger and male vs. female cohorts to investigate sex and age differences in [18F]nifene binding. Distribution volume ratios (DVRs) were calculated for brain regions with known nAChR expression and compared using a multiparameter linear regression model. There was a significant association between age and decreasing thalamic DVR (p = 0.01) with the most notable difference coming from the anterior nucleus of the thalamus (p < 0.001). Outside of the thalamus a higher [18F]nifene DVR was observed with increasing age in the cerebellar grey matter (p = 0.01). No significant sex differences were observed using our linear model after multi-comparison correction. These results support including age in the experimental design and analysis of the α4β2* nAChR system in research and clinical applications.

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.

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).

Enhancing diagnostic accuracy for iron deficiency in pregnant women through mean reticulocyte volume.

Women are more prone to iron deficiency (ID) anemia when pregnant. The diagnostic use of mean reticulocyte volume (MRV) in identifying ID anemia during pregnancy has not been thoroughly investigated. The objective of this study is to evaluate the effectiveness of MRV in diagnosing ID in pregnant women. Firstly, MRV of 20 healthy female volunteers (healthy group) was measured on specific days for one month. Subsequently, clinical data from 724 pregnant women were thoroughly examined. These women were divided into two groups: 282 with ID (research group) and 442 without ID (control group). Parameters such as MRV, reticulocyte hemoglobin equivalent (RHE), red blood cell volume distribution width-standard deviation (RDW-SD), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), hematocrit (HCT), reticulocyte count (RET), MRV/MCV ratio, and serum ferritin (SF) were analyzed and compared. MRV remained consistent over a period of one month for 20 healthy individuals. In addition, there were significant differences in MRV, RHE, RDW-SD, MCV, MCH, MCHC, HCT, RET, and MRV/MCV between the research group and control group. The receiver operating characteristic (ROC) analysis showed that the areas under the curve (AUCs) for these measures were as follow: 0.840, 0.837, 0.676, 0.654, 0.639, 0.602, 0.571, 0.550, and 0.816, respectively. Ultimately, there was a substantial disparity in MRV prior to and following therapy with oral iron treatments. In healthy women, MRV remains stable and is a reliable ID marker, which can be used to assess oral iron treatment effectiveness during pregnancy.

Precisely Constructing Superlattices of Soft Giant Molecules via Regulating Volume Asymmetry.

Soft matters, particularly giant molecular self-assembly, have successfully replicated complex structures previously exclusive to metal alloys. These superlattices are constructed from mesoatoms─supramolecular spherical motifs of aggregated molecules, and the formation of superlattices critically depends on the volume distributions of these mesoatoms. Herein, we introduce two general methods to control volume asymmetry (i.e., the volumes' ratio of the largest to smallest mesoatoms, VL/VS) within giant molecular self-assembly. Leveraging the spontaneous increase in the mesoatomic volume ratio in unary systems and self-sorted binary blends, we systematically adjust the volume asymmetry from 1.0 to 9.0 across 24 unary systems and 56 binary blends of giant molecules, uncovering the formation of various superlattices, including BCC, Frank-Kasper A15, σ, Laves C14, C15, NaZn13, AlB2, and notably, the first NaCl like superlattice in homogeneous soft matter self-assembly. A geometric-based analysis, combined with experimental results, further establishes a quantitative relationship between volume asymmetry and the corresponding superlattice formations, thus laying a solid foundation for superlattice engineering within giant molecular systems to mimic and even beyond metal alloys. The lattice parameters of various unit cells range from approximately 5 to 20 nm. Our investigation in giant molecules could guide the advancement of mesoscopic, periodic soft matter materials.

Comparing the coagulation and platelet parameters of womenwith premature ovarian insufficiency with those of age-matched controls: A case-control study.

This study aimed to compare the coagulation and platelet parameters in women with spontaneous premature ovarian insufficiency (POI) with those in age-matched controls. This case-control study recruited 202 women with POI and 202 age-matched women with benign gynecological diseases as controls. Coagulation parameters, including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), and thrombin time (TT), fibrinogen, and platelet parameters, including platelet count (PLT), mean platelet volume (MPV), plateletcrit (PCT), and platelet distribution width (PDW), were compared between women with POI and controls. Factors associated with coagulation and platelet parameters were also analyzed in women with POI. In women with POI, higher fibrinogen levels and PDW, lower PLT, MPV, and PCT levels, and shorter TT were observed (p < 0.001). Linear regression analysis further revealed that women with POI were more likely to exhibit increased serum fibrinogen levels (β = 0.465, 95% confidence interval [CI] 0.366-0.564) and PDW (β = 0.340, 95% CI 0.300-0.379), decreased TT (β = -1.101, 95% CI -1.233--0.969), PLT (β = -50.985, 95% CI -65.087--36.882), MPV (β = -1.498, 95% CI -1.875 to -1.120), PCT levels (β = -0.084, 95% CI -0.095--0.973). Additionally, follicle-stimulating hormone levels were positively associated with fibrinogen levels in women with POI. There were no statistically significant differences in PT, INR, and APTT between women with POI and controls. Women with POI exhibited decreased platelet numbers, abnormal platelet morphology, and elevated fibrinogen concentrations, potentially implicating POI's etiopathogenesis or contributing to an increased risk of cardiovascular disease in women with POI. No coagulation abnormalities were observed in women with POI.

An in vivo examination of the relationship between metabotropic glutamate receptor 5 and suicide attempts in people with borderline personality disorder

BackgroundBorderline Personality Disorder (BPD) is a serious psychiatric condition, associated with a high risk for suicide attempts and death by suicide. However, relatively little is known about the pathophysiology of BPD. The metabotropic glutamate receptor type 5 (mGlu5) has been specifically implicated in the pathophysiology of BPD and suicide attempts, with more general roles in emotion regulation, social and cognitive functioning, and pain processing. Here, we examined the relationship between mGlu5 availability, BPD, and suicide attempts in vivo for the first time. MethodsEighteen individuals with BPD, and 18 age-, sex-, and smoking-status matched healthy (HC) and 18 clinical comparison controls with major depressive disorder (MDD) completed comprehensive clinical assessments and participated in an [18F]FPEB positron emission tomography (PET) scan to measure mGlu5 availability. Volume of distribution (VT) in the frontolimbic circuit implicated in BPD pathophysiology was the PET outcome measure. ResultsWe observed significantly higher frontolimbic mGlu5 availability in BPD compared to both HC (p=.009, d=0.84, 18.43% difference), and MDD (p=.03, d=0.69, 15.21% difference). In the BPD, but not MDD group, higher mGlu5 availability was also associated with history of suicide attempts (SA; 19-25% higher, p’s=.005-.02). Further, mGlu5 availability was positively correlated with risk factors for suicide (e.g., sexual victimization, perceived burdensomeness) in BPD-SA group. ConclusionsResults show higher mGlu5 availability in BPD and suicide attempt for the first time. Our preliminary findings suggest mGlu5 may be a critical treatment target for BPD symptoms, including suicide attempts, and warrant further investigation in larger samples.

Longitudinal changes in regional fat and muscle composition and cardiometabolic biomarkers over 5 years of hormone therapy in transgender individuals.

Longitudinal studies investigating hormone therapy in transgender individuals are rare and often limited to 1- to 2-year follow-up periods. We examined changes in body composition, muscle volumes, and fat distribution as well as muscle strength, arterial stiffness, and cardiometabolic biomarkers in both transgender men (TM; n=17, age 25±5 years) and transgender women (TW; n=16, age 28±5 years) at baseline and after 1 and 5-6 years of hormone therapy in a longitudinal prospective cohort design. Whole-body and regional fat and muscle volumes were analyzed using magnetic resonance imaging, and blood samples were taken. Skeletal muscle size increased in TM (21% after 6 years) and decreased in TW (7% after 5 years). Muscle strength increased 18% after 6 years in TM (p=0.003) but was statistically unchanged in TW. Muscle fat infiltration changed (p<0.05) almost completely toward the affirmed sex phenotype after 1 year of therapy in both TM and TW. The most notable changes in fat volume distribution were that TW increased total adiposity but decreased visceral fat volume, whereas TM showed increased visceral fat (70%) and liver fat but relatively stable total adipose tissue levels. Although arterial stiffness and blood pressure did not change, there was a significant increase in triglyceride and LDL cholesterol levels and a decrease in HDL levels in TM after 6 years. These unique longitudinal data underscore the importance of continued clinical monitoring of the long-term health effects of gender-affirming hormone therapy in both TW and, perhaps especially, TM.

Prediction of human pharmacokinetic parameters incorporating SMILES information.

This study aimed to develop a model incorporating natural language processing analysis for the simplified molecular-input line-entry system (SMILES) to predict clearance (CL) and volume of distribution at steady state (Vd,ss) in humans. The construction of CL and Vd,ss prediction models involved data from 435 to 439 compounds, respectively. In machine learning, features such as animal pharmacokinetic data, in vitro experimental data, molecular descriptors, and SMILES were utilized, with XGBoost employed as the algorithm. The ChemBERTa model was used to analyze substance SMILES, and the last hidden layer embedding of ChemBERTa was examined as a feature. The model was evaluated using geometric mean fold error (GMFE), r2, root mean squared error (RMSE), and accuracy within 2- and 3-fold error. The model demonstrated optimal performance for CL prediction when incorporating animal pharmacokinetic data, in vitro experimental data, and SMILES as features, yielding a GMFE of 1.768, an r2 of 0.528, an RMSE of 0.788, with accuracies within 2-fold and 3-fold error reaching 75.8% and 81.8%, respectively. The model's performance in Vd,ss prediction was optimized by leveraging animal pharmacokinetic data and in vitro experimental data as features, yielding a GMFE of 1.401, an r2 of 0.902, an RMSE of 0.413, with accuracies within 2-fold and 3-fold error reaching 93.8% and 100%, respectively. This study has developed a highly predictive model for CL and Vd,ss. Specifically, incorporating SMILES information into the model has predictive power for CL.

Vaginal Misoprostol Pharmacokinetic Changes in Obese Parturient Women Who Presented Labor Induction Failure.

Clinical experience shows an increased duration of labor in obese parturient women. It is unclear if this population should receive the same dose of vaginal misoprostol for induction of labor as non-obese parturient women. We investigate the influence of obesity on the pharmacokinetics and placental transfer of the metabolite misoprostol acid in parturient women. Parturient women (n = 40) were enrolled and received misoprostol 25 µg/6 h vaginally and were allocated into two groups according to the pre-pregnancy body mass index (BMI <30 kg/m2 non-obese, n = 18 or BMI >30 kg/m2 obese, n = 22) or according to the labor induction outcome (failure [n = 10] or success [n = 30]). Blood collection for pharmacokinetic study occurred after the first misoprostol dose. The pharmacokinetic parameters obtained in non-obese parturient women were not statistically different from those obtained in obese group (PValue > .05). However, when the parturient women were grouped by the labor induction outcome, the failed labor induction group presented a higher (median [interquartile range]) BMI (44.4 [34.6-47.9] vs 33.7 [28.9-36.5] kg/m2) (PValue = .0017), lower Cmax (11.5 [4.82-22.2] vs 22.8 [14.2-30.8] pg/mL) (PValue = .0308) and not statistically different AUC0-6 (31.8 [13.4-61.5] vs 53.4 [35.4-77.7]) pg·h/mL) (PValue = .0580) and tmax (2.50 [1.19-4.25] vs 3.00 (1.88-5.00) h (PValue = .3198) when compared with parturient women who presented successful labor induction. This data suggests a higher loading dose (higher volume of distribution) and unchanged maintenance dose (unchanged AUC0-6) of misoprostol for this population. Further studies are required to investigate the efficacy and safety of higher misoprostol loading doses for this population.

Phase I pharmacokinetic study of etmaben, a malonic acid derivative

Introduction. Etmaben is a malonic acid derivative that has shown cardiotropic activity and is a promising candidate for treating ischemic heart disease and chronic heart failure. It is currently undergoing Phase I clinical trials, and its pharmacokinetics have not yet been studied in humans.Aim. The aim of the study is to investigate the pharmacokinetics of Etmaben, film-coated tablets, 300 mg (SPCPU, Russia) in healthy volunteers after fasting administration of different doses following both single and multiple dosing over a 7-day period.Materials and methods. The open-label, non-randomized clinical trial involved 48 healthy volunteers divided into 6 cohorts. Volunteers in cohort 1 received a single dose of 600 mg of etmaben, cohort 2 received 900 mg, and cohort 3 received 1200 mg. Cohorts 4, 5, and 6 received daily doses of 600 mg, 900 mg, and 1200 mg, respectively. Plasma concentrations of etmaben were measured using high-performance liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using Microsoft Excel with the Boomer extension (Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, CA 92606, USA).Results and discussion. Pharmacokinetic parameters were calculated for 6 cohorts of 8 volunteers after single and multiple dosing of Etmaben at doses of 600, 900, and 1200 mg. The maximum plasma concentration (Cmax) of etmaben was reached on average within 0.5 h. Cmax values ranged from 2.708 ± 1.461 µg/mL to 19.871 ± 4.415 µg/mL. The maximum half-life was 0.874 ± 0.236 h, with an elimination rate constant not exceeding 1.053 ± 0.149 h–1. The mean residence time (MRT) of etmaben in plasma did not exceed 1.527 ± 0.272 h. The average volume of distribution was above 45 L, and clearance exceeded 42 L, indicating significant tissue distribution and rapid drug elimination. Due to low area under the curve values and high elimination rates, the accumulation of etmaben is minimal.Conclusion. Pharmacokinetic parameters were calculated, and averaged pharmacokinetic profiles were constructed in linear and semilogarithmic coordinates after single and multiple dosing of various etmaben doses. This study represents the first investigation of etmaben pharmacokinetics in humans, paving the way for subsequent clinical trials.

Population Pharmacokinetics of Ensitrelvir in Healthy Participants and Participants with SARS-CoV-2 Infection in the SCORPIO-SR Study.

Ensitrelvir, a novel oral inhibitor of the 3C-like protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has shown efficacy and safety in participants with mild to moderate coronavirus disease 2019 (COVID-19) with once-daily multiple doses of 375mg on day 1 followed by 125mg on days 2-5. The aims of this study were to characterize the pharmacokinetics of ensitrelvir and to explore its exposure-response relationships on the dose regimen. Pharmacokinetic data, including 8034 plasma concentration datasets from 2060 participants, from two phase I and one phase II/III study in healthy participants and participants infected with SARS-CoV-2 were used to develop a population pharmacokinetic model. The correlation between exposure and drug response was evaluated using observed plasma concentrations and estimated pharmacokinetic parameters as pharmacokinetic indexes and viral RNA as drug response. A two-compartment model with a first-order absorption model effectively described plasma ensitrelvir concentrations. The effects of body weight on clearance and volume of distribution and of food conditions and formulation on the absorption rate constant were selected as significant covariates. The efficacy indexes changed in the active group, but the responses were similar across the exposure range in the phase II/III study (SCORPIO-SR) regardless of the effects of the pharmacokinetic covariates. Population pharmacokinetics revealed that body weight is the most important covariate in the pharmacokinetics of ensitrelvir. The antiviral effect, independent of ensitrelvir exposure, was demonstrated on the current dose regimen for treatment of SARS-CoV-2 infection.

Hematological parameters of the European hake (Merluccius merluccius) in Toroneos Gulf, northern Greece: A case study

Background: The European hake (Merluccius merluccius) is a commercially valuable demersal species widely distributed in the Mediterranean Sea. Assessing the condition of fish populations in their natural habitats is challenging due to the lack of reliable reference points. Objective: This study aimed to utilize hematological analysis as an economical method to evaluate the physiological and health status of European hake, addressing the gap in hematological data for this species. Methods: Blood samples were collected from the caudal vein of 40 adult European hakes caught from the Toroneos Gulf (northern Greece) using a commercial bottom otter trawl. An automated hematological analyzer was used to assess hematological parameters alongside biometric and biological indices. Results: Female hakes showed significantly higher white blood cell (WBC) counts, thrombocyte (TC) counts, and red cell distribution width (RDW) than their male counterparts. Strong correlations were observed among various hematological parameters, notably between WBC and red blood cells (RBCs), hematocrit (Ht), and hemoglobin (Hb); between RBC and both Ht and Hb; between TC and both mean platelet volume and platelet distribution width (PDW); and between mean corpuscular Hb concentration and RDW. Significant differences were noted in RBCs, Hb, and Ht compared to data from wild-caught European hake populations in Argentina and Denmark. Both trawling depth and duration were found to significantly affect RBC, WBC, Hb, and Ht values, while having no notable impact on TC. Fish captured at an average depth of 80 m and with a trawling duration of 30 min exhibited significantly elevated hematological indices. Conclusion: This study demonstrates that hematological analysis is a valuable, cost-effective tool for assessing the physiological and health status of European hake populations in the Mediterranean. Notable differences in hematological parameters based on sex, as well as significant correlations among key blood metrics, underscore the importance of understanding species-specific hematological profiles. The influence of trawling depth and duration on certain blood parameters highlights the need for standardized sampling protocols in population health assessments. These findings contribute essential baseline hematological data for European hake, facilitating more informed fisheries management and conservation strategies.

Effect of Body Size on Plasma and Tissue Pharmacokinetics of Danofloxacin in Rainbow Trout (Oncorhynchus mykiss).

Danofloxacin is a fluoroquinolone antibiotic approved for use in fish. It can be used for bacterial infections in fish of all body sizes. However, physiological differences in fish depending on size may change the pharmacokinetics of danofloxacin and therefore its therapeutic efficacy. In this study, the change in the pharmacokinetics of danofloxacin in rainbow trout of various body sizes was revealed for the first time. The objective of this investigation was to compare the plasma and tissue pharmacokinetics of danofloxacin in rainbow trout of different body sizes. The study was conducted at 14 ± 0.5 °C in fish of small, medium, and large body size and danofloxacin was administered orally at a dose of 10 mg/kg. Concentrations of this antimicrobial in tissues and plasma were quantified by high performance liquid chromatography with ultraviolet detector. The plasma elimination half-life (t1/2ʎz), volume of distribution (Vdarea/F), total clearance (CL/F), peak concentration (Cmax), and area under the plasma concentration-time curve (AUC0-last) were 27.42 h, 4.65 L/kg, 0.12 L/h/kg, 2.53 µg/mL, and 82.46 h·µg/mL, respectively. Plasma t1/2ʎz, AUC0-last and Cmax increased concomitantly with trout growth, whereas CL/F and Vdarea/F decreased. Concentrations in liver, kidney, and muscle tissues were higher than in plasma. Cmax and AUC0-last were significantly higher in large sizes compared to small and medium sizes in all tissues. The scaling factor in small, medium, and large fish was 1.0 for bacteria with MIC thresholds of 0.57, 0.79, and 1.01 µg/mL, respectively. These results show that therapeutic efficacy increases with body size. However, since increases in danofloxacin concentration in tissues of large fish may affect withdrawal time, attention should be paid to the risk of tissue residue.

Microscopic effect and mechanism of spray polyurea modifier on the asphalt binder: Experimental characterization and molecular dynamics simulations

To investigate the impact of spray polyurea (SPUA) modifiers on the microstructure and performance of asphalt, SPUA powder prepared by cryogenic grinding was selected as modifier to explore the microscopic mechanisms of spray polyurea modified asphalt. Initially, the morphological characteristics of the SPUA modifiers were systematically characterized using morphological methods. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were conducted to examine the effects of SPUA on the thermodynamic properties of asphalt. Finally, molecular dynamics simulations were utilized to model SPUA modified asphalt at different concentrations. Critical parameters such as cohesive energy density, solubility parameters, interaction energy, free volume, and radial distribution function (RDF) were analyzed to elucidate the microscopic mechanisms underlying the experimental results. The results indicate that the surface morphology of SPUA includes several pore structures, which enhance the tight and continuous bonding at the SPUA asphalt interface, thereby enhancing the microstructural stability of the modified asphalt. Additionally, incorporating SPUA increased the decomposition temperature of the asphalt binder, improving its thermal stability. This phenomenon is further validated by molecular dynamics simulations, which show that with increasing amounts of polyurethane, both the cohesive energy density and interaction energy of the asphalt system significantly increase, thereby enhancing the structural strength of the asphalt system. However, while low SPUA concentrations enhance the surface roughness of the asphalt, excessive SPUA may disrupt the uniform dispersion of the asphalt binder. This leads to a reduction in the difference in solubility parameters between the two components, diminishing compatibility, and decreasing the free volume fraction of the asphalt while increasing the peak of the radial distribution function curve. Such changes adversely affect the flowability and stability of the modified asphalt.

A Population Pharmacokinetic Study to Evaluate Doxorubicin Exposure Across All Age Groups.

The effect of age on doxorubicin pharmacokinetics remains inconclusive, especially in patients at the extremes of the age spectrum. We developed a population pharmacokinetic model to further investigate the impact of age on the pharmacokinetics of doxorubicin. A three-compartment model, incorporating allometric scaling was developed to describe doxorubicin pharmacokinetics across all ages. First, the effect of age in young patients was investigated, by adding a maturation function on clearance (CL), the central compartment (V1) and peripheral compartments (V2 and V3). Second, the impact of ageing was investigated by adding a maximal effect (Emax) function on CL, V1, V2, and V3. To investigate the overall impact of age on doxorubicin exposure, various simulations were conducted. A total of 168 patients (age: 0.11-90 years) with 555 doxorubicin samples were included. The maturation function was relevant for V1 and V2 (13.1 and 23.7L, respectively), leading to an increase in V1 and V2 with increasing age. In contrast, adding an Emax function only impacted V3 (1063L), resulting in a decrease of V3 with age. Simulations showed no clinically relevant difference in the exposure of doxorubicin between age groups. A population pharmacokinetic model with data across the age range showed that age predominantly affected volumes of distribution of the central and peripheral compartments. These effects were not considered to be clinically relevant based on performed simulations. This supports the use of currently used doxorubicin dosages of 1 mg/kg for infants and toddlers <10 kg and body surface area-based dosing for other patients.

Pharmacokinetics of Enteral Lormetazepam in Mechanically Ventilated ICU Patients with COVID-19: An Adjunct Sedative Study.

During the coronavirus disease 2019 (COVID-19) pandemic, sedative prescriptions surged, leading to shortages of midazolam. This study investigates lormetazepam as an adjunct sedative alternative to midazolam for mechanically ventilated patients with COVID-19. We aimed to determine the clinical pharmacokinetics (PK) of enterally administered lormetazepam and provide dosing recommendations. Critically ill patients with acute respiratory distress syndrome (ARDS) or COVID-19 requiring mechanical ventilation were enrolled in April 2020. Lormetazepam 2 mg every 12 h was administered enterally. Blood samples were collected to quantify lormetazepam and its glucuronide. PK analysis was conducted using a one-compartment model with the Edsim++ KinPop plugin. The primary PK parameters (means ± coefficient of variation [CV] %) for absorption constant (Ka), volume of distribution (Vd/F), and clearance (CL/F) were 6.4 h-1, 207 L/70 kg, and 14.5 L/h/kg0.75, respectively. Vd/F and CL/F median values were 2.64 L/kg and 2.53 mL/kg/min, respectively, with a half-life of 10.7 h. Lormetazepam's median ratio to its glucuronide was 11.5. Trough-guided dosing suggested alternatives of 0.92 mg three times daily, 1.62 mg twice daily, or 5.36 mg once daily. This is the first study to report a validated PK model for enterally administered lormetazepam as a sedative adjunct in critically ill adults on mechanical ventilation for ARDS and COVID-19. The model was internally validated using a bootstrap procedure. Adequate lormetazepam concentrations were achieved at prescribed doses, with no significant alterations in clearance or half-life. This population model may aid in dose optimization and sedation management for future intensive care unit (ICU) patients.