Excretion Rate Research Articles

Population pharmacokinetics and pharmacodynamics of nasal glucagon in patients with type 1 or 2 diabetes.

The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of glucagon after injectable or nasal administration and confirm the appropriate therapeutic dose of nasal glucagon (NG) for adult patients. Six clinical studies with PK and five clinical studies with PD (glucose) data were included in the analysis. Doses ranging from 0.5 to 6 mg NG, and 0.5 to 1 mg injectable glucagon were studied. A total of 6284 glucagon and 7130 glucose concentrations from 265 individuals (patients and healthy participants) were available. Population PK/PD modeling was performed using NONMEM. Glucagon exposure and glucose response were simulated for patients administered various doses of NG to confirm the optimal dose. Glucagon PK was well-described with a single compartment disposition with first-order absorption and elimination processes. Bioavailability of NG relative to injectable glucagon was 16%. Exposure-response modeling revealed that lower baseline glucose was associated with higher maximum drug effect. The carry-over effect from prior insulin administration was incorporated into the model through a time-dependent increase in elimination rate of glucose. Simulations showed that more than 99% of hypoglycemic adult patients would experience treatment success, defined as an increase in blood glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from nadir within 30 min after administration of NG 3 mg. The population PK/PD model adequately described the PK and PD profiles of glucagon after nasal administration. Modeling and simulations confirmed that NG 3 mg is the most appropriate dose for rescue treatment during hypoglycemia emergencies.

Surface basic site effect on CoLa/m-Al2O3 catalysts for dry reforming of methane

Dry reforming of methane (DRM) is a novel technology that enables the direct utilization of greenhouse gases (CH4 and CO2) for the production of value-added products. In the DRM reaction, the acid-base characteristics of the catalyst support play a pivotal role in determining the performance of the catalyst. In this study, a series of Co-based catalysts with different alkali earth metal-modified Al2O3 composite supports, specifically m-Al2O3 (m=Ca, Mg, and Ba), were prepared using the impregnation method. Various characterization techniques were employed to investigate the impact of alkaline site modulation on the support surface with respect to anti-sintering and anti-coking properties. The results demonstrate that the m-Al2O3 composite support catalysts, prepared with Mg and Ca modulation, exhibit an abundance of basic sites and oxygen vacancies. This promotes the adsorption and activation of CO2, enhances the rate of carbon elimination, and effectively addresses carbon deposition and metal sintering issues. Notably, the CoLa/Mg-Al2O3 catalyst shows the highest performance under reaction conditions of 750 °C, with CH4 and CO2 conversions reaching 92.3 % and 97.5 %, respectively. On the other hand, the CoLa/Ba-Al2O3 catalysts display poor performance in dry reforming. Kinetic studies indicate that CoLa/Mg-Al2O3 catalyst significantly reduce the apparent activation energy required for CH4 and CO2 cracking. Furthermore, it is demonstrated that the introduction of alkali earth metals can promote the dissociation of CH4 and CO2.

The combination of nanobubble aeration and iron-based multi-carbon source composites achieves efficient aquaculture wastewater nitrogen removal

The primary constraints for efficient nitrogen removal in aquaculture ponds by indigenous aerobic denitrifiers are oxygen depletion in sediment and the shortage of electron donors. This study innovatively combined nanobubble aeration with iron-based multi-carbon source composites to stimulate aerobic denitrifiers, significantly improving the sediment's oxygen level and supplementing the electron donors of the system. Compared with the systems that incorporated multi-carbon source composites (MCSC) or iron-based multi-carbon source composites (IMCSC) under diffused air aeration conditions, the system that employed nanobubble aeration and iron-based multi-carbon source composites (NIMCSC) demonstrated an increase in total nitrogen (TN) elimination rate by 14.07% and 7.46%, respectively, reaching 89.75%. Microbial community analysisrevealed that the NIMCSC systemenriched the mixotrophic aerobic denitrifiers and fostered a symbiotic relationship among the bacterial communities. Moreover, compared with the MCSC and IMCSC systems, the NIMCSC system highlighted a significant increase in the average abundance of key indigenous aerobic denitrifiers. Meanwhile, the production and transfer process of electrons were stimulated, providing more energy and electron donors and assisting various abundant key functional enzymes to achieve efficient mixotrophic aerobic denitrification in the NIMCSC system. This study presenteda novel approach to achieve efficient aquaculture wastewater nitrogen removal.

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.

Research on Risk Propagation in Fresh E-commerce Supply Chain Based on Complex Networks

In recent years, the rapid growth of the fresh e-commerce industry has introduced several potential risk factors to the supply chain that necessitate preventative measures. This paper aims to study the risk propagation within the fresh e-commerce supply chain and propose strategies for risk control. Firstly, a dual local world fitness network model is constructed by combining the fitness model with the local world model. This model is then validated, showing consistency with the actual network. Building upon this, an improved SEIRS risk propagation model is developed, and the basic reproduction number is calculated to simulate the risk propagation within the fresh e-commerce supply chain. The results indicate that the degree of risk propagation is positively correlated with the initial infection rate, risk outbreak rate, and loss of immunization rate, while negatively correlated with the risk recovery rate and risk elimination rate.

Statistical Design and Optimization of Nano-Transfersomes Based Chitosan Gel for Transdermal Delivery of Cefepime

Objectives: This research aimed to overcome challenges posed by cefepime excessive elimination rate and poor patient compliance by developing transdermal delivery system using nano-transfersomes based chitosan gel. Methods: Rotary evaporation-sonication method and the Box-Behnken model were used to prepare cefepime loaded nano-transfersomes (CPE-NTFs). The physiochemical characterization of CPE-NTFs were analyzed including DLS, deformability index, DSC and antimicrobial study. Optimized CPE-NTFs loaded into chitosan gel and appropriately characterized. In vitro release, ex vivo and in vivo studies were performed. Results: The CPE-NTFs were physically stable with particle size 222.6 ± 1.8 nm, polydispersity index 0.163 ± 0.02, zeta potential -20.8 ± 0.1 mv, entrapment efficiency 81.4 ± 1.1% and deformability index 71 ± 0.2. DSC analysis confirmed successful drug loading and thermal stability. FTIR analysis showed no chemical interaction among the excipients of CPE-NTFs gel. The antibacterial activity demonstrated a remarkable reduction in the minimum inhibitory concentration of cefepime when incorporated into nano-transfersomes. CPE-NTFs based chitosan gel (CPE-NTFs gel) showed significant physicochemical properties. In vitro release studies exhibited sustained release behavior over 24 hours, and ex vivo studies indicated enhanced permeation and retention compared to conventional cefepime gel. In vivo skin irritation studies confirmed CPE-NTFs gel was non-irritating and biocompatible for transdermal delivery. Conclusion: This research showed nano-transfersomes-based chitosan gel is a promising approach for cefepime transdermal delivery and provides sustained release of cefepime.

Analysis of the most popular online BAC calculators = Analiza najpopularniejszych dostępnych w sieci „kalkulatorów trzeźwości”

In order to check their sobriety after drinking alcohol, drivers can use applications available online that perform prospective estimation of alcohol content, called ‘alcomat online’ or ‘BA C calculators’. The aim of the study was to analyse the method of performing calculations using ‘BA C calculators’ available on the Internet and to assess their reliability. The five most popular ‘calculators’ found in the Google search engine and a commercial one were analysed. The applications were tested by entering data on 10 cases of alcohol consumption by people were tested for alcohol content in exhaled air using the Alcotest 7510 analyser and alcohol curves were plotted for them. Then, real ethanol concentrations and complete ethanol elimination times for these people were compared with values calculated by the applications. The analysed ‘calculators’ base their calculations on various principles. Both the maximum alcohol concentrations and the time of their occurrence varied among the applications, but all seem to use the alcohol distribution coefficient established by Widmark. The use of individual elimination rates ranging from 0.12 to even 0.3‰/h was also observed. The time for complete alcohol elimination indicated by the applications was in most cases longer than the actual time. Online applications such as the ‘BA C calculator’ available to Polish users may be helpful tools for determining the time of complete elimination of alcohol from the body. However, due to the different calculation methods used in applications, which sometimes lead to different conclusions, they should be approached with great caution. These applications will not replace reliable sobriety tests, e.g. analysis of exhaled air.

A Comprehensive Study to Determine the Residual Elimination Pattern of Major Metabolites of Amoxicillin–Sulbactam Hybrid Molecules in Rats by UPLC–MS/MS

Amoxicillin and sulbactam are widely used in animal food compounding. Amoxicillin–sulbactam hybrid molecules are bicester compounds made by linking amoxicillin and sulbactam with methylene groups and have good application prospects. However, the residual elimination pattern of these hybrid molecules in animals needs to be explored. In the present study, the amoxicillin–sulbactam hybrid molecule (AS group) and a mixture of amoxicillin and sulbactam (mixture group) were administered to rats by gavage, and the levels of the major metabolites of amoxicillin, amoxicilloic acid, amoxicillin diketopiperazine, and sulbactam were determined by UPLC–MS/MS. The residue elimination patterns of the major metabolites in the liver, kidney, urine, and feces of rats in the AS group and the mixture group were compared. The results showed that the total amount of amoxicillin, amoxicilloic acid, amoxicillin diketopiperazine, and the highest concentration of sulbactam in the liver and kidney samples of the AS group and the mixture group appeared at 1 h after drug withdrawal. Between 1 h and 12 h post discontinuation, the total amount of amoxicillin, amoxicilloic acid, and amoxicillin diketopiperazine in the two tissues decreased rapidly, and the elimination half-life of the AS group was significantly higher than that in the mixture group (p < 0.05); the residual amount of sulbactam also decreased rapidly, and the elimination half-life was not significantly different (p > 0.05). In 72 h urine samples, the total excretion rates were 60.61 ± 2.13% and 62.62 ± 1.73% in the AS group and mixture group, respectively. The total excretion rates of fecal samples (at 72 h) for the AS group and mixture group were 9.54 ± 0.26% and 10.60 ± 0.24%, respectively. These results showed that the total quantity of amoxicillin, amoxicilloic acid, and amoxicillin diketopiperazine was eliminated more slowly in the liver and kidney of the AS group than those of the mixture group and that the excretion rate through urine and feces was essentially the same for both groups. The residual elimination pattern of the hybrid molecule in rats determined in this study provides a theoretical basis for the in-depth development and application of hybrid molecules, as well as guidelines for the development of similar drugs.

Laparoscopic-assisted microwave ablation in treatment of small hepatocellular carcinoma: safety and efficacy in comparison with laparoscopic hepatectomy

Laparoscopic-assisted microwave ablation (LAMWA), as one of the locoregional therapies, has been employed to treat hepatocellular carcinoma (HCC). This study aims to compare the efficacy and safety of LAMWA and laparoscopic hepatectomy in the treatment of small HCC.This study included 140 patients who met the inclusion criteria. Among them, 68 patients received LAMWA and 72 patients underwent laparoscopic hepatectomy. The perioperative condition, liver function recovery, the alpha fetoprotein (AFP) level, morbidities, hospitalization time, overall survival (OS), disease-free survival (DFS) and recurrence rate between the two groups were compared. The rate of complete elimination of tumor tissue was 100% and the AFP level was returned to normal within 3 months after surgery in both groups (P > 0.05). The mean alanine transaminase (ALT) and aspartate transaminase (AST) peak in the LAMWA group was lower than that in the laparoscopic hepatectomy group (259.51 ± 188.75 VS 388.9 ± 173.65, P = 0.000) and (267.34 ± 190.65 VS 393.1 ± 185.67, P = 0.000), respectively. The mean operation time in the LAMWA group was shorter than that in the laparoscopic hepatectomy group (89 ± 31 min VS 259 ± 48 min, P = 0.000). The blood loss in the LAMWA group was less than that in the laparoscopic hepatectomy group (58.4 ± 64.0 ml VS 213.0 ± 108.2 ml, P = 0.000). Compared with the laparoscopic hepatectomy group, patients in the LAMWA group had lower mean hospital stay (4.8 ± 1.2d VS 11.5 ± 2.9d, P = 0.000). The morbidities of the LAMWA group and the hepatectomy group were 14.7%(10/68) and 34.7%(25/72), respectively (P = 0.006). The one-, three-, and five-year OS rates were 88.2%, 69.9%, 45.6% for the LAMWA group and 86.1%, 72.9%, 51.4% for the laparoscopic hepatectomy group (P = 0.693). The corresponding DFS rates for the two groups were 76.3%, 48.1%, 27.9% and 73.2%, 56.7%, 32.0% (P = 0.958). Laparoscopic-assisted microwave ablation is a safe and effective therapeutic option for selected small HCC.

Physiological Changes in Nickel-exposed Nile Tilapia Oreochromis niloticus during Exposure and Recovery Periods

Heavy metals are a significant problem in aquatic ecosystems as they are toxic and tend to accumulate, immediately affecting fish physiology. The present investigation was carried out to evaluate the sub-lethality of Nickel chloride on fingerlings of Nile tilapia, Oreochromis niloticus on long-term exposure to it is below safe concentrations1/fifth (9.39 ppm) and 1/10th (4.69 ppm). The physiological studies revealed a significant reduction in Oxygen Consumption Rate (OCR), Ammonia-N Excretion Rate (AER), Oxygen Rate (O: R) and Food Consumption Rate (FCR) and behavioural changes during accumulation and depuration phases. Limited recovery was obtained in all the physiological parameters after depuration for 28 days from the end of the accumulation period.

Note on importance of correct stoichiometric assumptions for modeling of monoclonal antibodies.

Pharmacokinetic modeling of monoclonal antibodies (mAbs) with non-linear binding is based on equations of the target-mediated drug disposition (Mager and Jusko, J Pharmacokinet Pharmacodyn 28:507-532, 2001). These equations demonstrated their utility in countless examples and drug development programs. The model assumes that the mAb drug and the target have only one binding site each while, in reality, most antibodies have two binding sites. Thus, the currently used model does not correspond to the biological process that it aims to describe. The correct mechanistic model should take into account both binding sites. We investigated, using simulations, whether this discrepancy is important and when it is advisable to use a model with correct stoichiometric 2-to-1 ratio. We show that for soluble targets when elimination rate of the drug-target complex is comparable with the elimination rate of the drug or lower, and when measurements of both total drug and total target concentrations are available, the model with 1-to-1 (monovalent) binding cannot describe data simulated from the model with 2-to-1 (bivalent) binding. In these cases, models with correct stoichiometric assumptions may be necessary for an adequate description of the observed data. Also, a model with allosteric binding that encompasses both 2-to-1 and 1-to-1 binding models as particular cases was proposed and applied. It was shown to be identifiable given the detailed concentration data of total drug and total target.

Integrated models of population pharmacokinetics and exposure response to optimize dosage regimen for anaprazole sodium in duodenal ulcer

Anaprazole sodium enteric-coated tablet is a novel proton pump inhibitor which has been approved for the treatment of duodenal ulcer. The aim of this study is to provide reliable information for the design of an optimal dosage regimen. Population pharmacokinetics and exposure-response models were integrated to evaluate the pharmacokinetic parameters and covariates of Anaprazole and its metabolite M21-1, and subsequently provided dosage suggestions based on clinical trials and simulation data. A pharmacokinetic model incorporating two-compartment for the parent drug and one-compartment for the metabolite, with both first-order and zero-order mixed absorption was used to describe the pharmacokinetics of Anaprazole and M21-1. Age emerged as a significant covariate affecting the elimination rate constant of M21-1, with clearance decreasing as age advances. No correlation was observed between the pharmacokinetics of Anaprazole or M21-1 and the adverse reactions under the current dosages. BMI might be the influence factor of the mild gastrointestinal adverse reactions. Meanwhile, Anaprazole had a good healing rate (94.0 %) in duodenal ulcer patients and the exposure-response analysis indicated that the cured results were not influenced by the exposure parameters of parent drug or metabolite. In conclusion, the drug is safe when dosing between 20 and 100 mg once a day.

Safety, pharmacokinetics, and food-effect of pivmecillinam after single- and multiple-dose in healthy Chinese subjects: a phase I study.

Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400mg (n = 12); group 3-single dose study with pivmecillinam 600mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600mg) or multiple-dose (400mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.

Iodine metabolism in urine and breast milk among lactating women with adequate iodine

BackgroundIn lactating women, iodine metabolism is regulated and maintained by the kidneys and mammary glands. Limited research exists on how iodine absorbed by lactating women is distributed between the kidneys and breasts. ObjectiveThis study aimed to accurately evaluate the total iodine intake (TII), urinary iodine excretion (UIE), and breast milk iodine excretion (BMIE) in lactating women and explore the relationship between TII and total iodine excretion (TIE). MethodsThe 7-day iodine metabolism study was conducted on 41 lactating women with a mean age of 30 years in Yuncheng and Gaoqing, China, from December 2021 to August 2023. TII and TIE were calculated by measuring the iodine content in food, water, 24-h urine, feces, and breast milk. The urinary iodine excretion rate (UIER), breast milk iodine excretion rate (BMIER), and partitioning of iodine excretion between urine and breast milk were determined. ResultsIodine metabolism studies were performed for 285 days. The median TII and TIE values were 255 and 263 μg/d, respectively. With an increase in TII, UIER, and BMIER, the UIE and BMIE to TII ratio exhibited a downward trend. The median UIER, BMIER, and proportion of iodine excreted in urine and breast milk were 51.5%, 38.5%, 52%, and 37%, respectively. When the TII was <120 μg/d, the BMIER decreased with the increase of the TII (β, -0.90, 95% CI: -1.08, -0.72). ConclusionsWhen maternal iodine intake is low, the proportion in breast milk increases, ensuring sufficient iodine nutrition for infants. In addition, the UIE of lactating women with adequate iodine levels was higher than their BMIE.

Towards process-based modelling and parameterisation of bioaccumulation in humans across PFAS congeners

Per- and polyfluoroalkyl substances (PFAS) are a large class of stable toxic chemicals which have ended up in the environment and in organisms in significant concentrations. Toxicokinetic models are needed to facilitate extrapolation of bioaccumulation data across PFAS congeners and species. For the present study, we carried out an inventory of accumulation processes specific for PFAS, deviating from traditional Persistent Organic Pollutants (POPs). In addition, we reviewed toxicokinetic models on PFAS reported in literature, classifying them according to the number of compartments distinguished as a one-compartment model (1-CM), two-compartment model (2- CM) or a multi-compartment model, (multi-CM) as well as the accumulation processes included and the parameters used. As the inventory showed that simple 1-CMs were lacking, we developed a generic 1-CM of ourselves to include PFAS specific processes and validated the model for legacy perfluoroalkyl acids. Predicted summed elimination constants were accurate for long carbon chains (>C6), indicating that the model properly represented toxicokinetic processes for most congeners. Results for urinary elimination rate constants were mixed, which might be caused by the exclusion of reabsorption processes (renal reabsorption, enterohepatic circulation). The 1-CM needs to be improved further in order to better predict individual elimination pathways. Besides that, more data on PFAS-transporter specific processes are needed to extrapolate across PFAS congeners and species.

Fate of synthetic chemicals in the agronomic insect pest Spodoptera littoralis: experimental feeding-contact assay and toxicokinetic model.

Insecticides prevent or reduce insect crop damage, maintaining crop quality and quantity. Physiological traits, such as an insect's feeding behavior, influence the way insecticides are absorbed and processed in the body (toxicokinetics), which can be exploited to improve species selectivity. To fully understand the uptake of insecticides, it is essential to study their total uptake and toxicokinetics independent of their toxic effects on insects. We studied the toxicokinetics (TK) of insecticidally inactive test compounds incorporating agro-like structural motifs in larvae of the Egyptian cotton leafworm (Spodoptera littoralis,Lepidoptera),and their distribution across all biological matrices, using laboratory experiments and modeling. We measured Spodoptera larval behavior and temporal changes of whole-body concentrations of test compounds during feeding on treated soybean leaf disks and throughout a subsequent depuration period. Differences in the distribution of the total quantities of compounds were found between the biological matrices leaf, larva, and feces. Rate constants for uptake and elimination of test compounds were derived by calibrating a toxicokinetic model to the whole-body concentrations. Uptake and elimination rate constants depended on the physicochemical properties of the test compounds. Increasing hydrophobicity increased the bioaccumulation potential of test compounds. Incomplete quantities in larval matrices indicated that some compounds may undergo biotransformation. As fecal excretion was a major elimination pathway, the variable time of release and number of feces pellets led to a high variability in the body burden. We provide quantitative models to predict the toxicokinetics and bioaccumulation potential of inactive insecticide analogs (parent compounds) in Spodoptera.

Assessing the impact of two conventional wastewater treatment plants on small streams with effect-based methods

Sixty percent of discrete surface water bodies in Europe do not meet the requirements for good ecological and chemical status and in Germany, the situation is even worse with over 90% of surface water bodies failing to meet the threshold. In addition to hydromorphological degradation, intensive land use and invasive species, chemical pollution is primarily considered to be responsible for the inadequate ecological status of the water bodies. As a quantitatively important source of micropollutants, wastewater treatment plants (WWTPs) represent an important entry path for chemical stressors. It is therefore important to analyze the effectiveness of the WWTPs in eliminating micropollutants and other chemical stressors to mitigate the negative impacts of the treated wastewater (WW) in aquatic ecosystems. Accordingly, in this study, we evaluated the impacts of two conventional, medium-sized WWTPs on their small receiving water systems in the southwestern region of Hessen in Germany during two sampling campaigns (spring and fall) using effect-based methods (EBM). We hypothesized that due to the insufficient elimination of micropollutants, a broad spectrum of toxic effects would be detected in conventionally treated WW and also in the receiving surface waters downstream the WWTPs. As EBMs a battery of in vitro assays and active biomonitoring using two in vivo assays were applied. The results supported our hypothesis and showed that the untreated WW had a very high baseline toxicity and also high endocrine and mutagenic activities. Conventional WW treatment, consisting of mechanical and biological treatment with nitrification, denitrification and phosphate precipitation, reduced baseline toxicity by more than 90% and endocrine activities by more than 80% in both WWTPs. Despite these high elimination rates, the remaining baseline toxicity, the endocrine, dioxin-like and mutagenic activities of the conventionally treated WW were so high that negative effects on the two receiving waters were to be expected. This was confirmed in the active monitoring with the amphipod Gammarus fossarum and the mudsnail Potamopyrgus antipodarum, as mortality of both species increased downstream of the WWTPs and reproduction in P. antipodarum was also affected. These results indicate that advanced WW treatment is needed to more effectively eliminate chemical stressors to prevent negative impacts of treated WW particularly in small receiving waters.

Analysis of current equine feeding practices in the netherlands and identification of potential nutrient leaching and environmental contamination factors

The aim of this study was to estimate the potential for nutrient leaching based on current feeding practices of horses in the Netherlands. An online survey of horse owners collected data on the demographics of the horses (n = 274) and feeding practices. The median age was 8 years, the majority being warmblood and geldings with a mean bodyweight of 542.4 ± 101.9 kg. Most horses (85 %) had access to a limited area of pasture (<200m2 per horse), with a median grazing time of 10 hours. Grass hay was the predominant conserved forage offered (77 %) within diets. Concentrate feeds were provided to most horses (93.8 %) as well as the dietary supplements (80 %). The majority of the horses were offered high levels of metabolizable energy (ME) (90 %), starch (mean 2.4 ± 0.8 g/kg bw) and sugar intake (mean 1.4 ± 1.2 g/kg bw) compared to NRC recommendations. The estimated potential nitrogen excretion per horse per day was 228 ± 134 g, or 8.47 kg of nitrogen per ton of manure. Consequently, the estimated daily fecal excretion rates of microminerals for each horse were as follows: Copper (Cu) at 141.0 ± 151.3 mg, Zinc (Zn) at 593.1 ± 504.4 mg, Manganese (Mn) at 957 ± 541.2 mg, and Cobalt (Co) at 2.3 ± 3.5 mg. The analysis indicated that many equine diets in the Netherlands offered excess ME, CP and the minerals Cu, Zn, Mn and Co. To mitigate these concerns, it is crucial to promote sustainable feeding practices and better educate horse owners.

Pharmacokinetics and pharmacodynamics of dextroketamine alone or combined with midazolam in Caiman crocodilus.

Pharmacokinetics studies of anesthetic agents are important for understanding of the pharmacology and metabolism of anesthetic agents in reptilians. This study was designed to examine the pharmacokinetic and pharmacodynamic properties of intravenous dextroketamine alone or combined with midazolam in Caiman crocodilus. Eight caimans were anesthetized with dextroketamine (10 mg/kg; group D) or dextroketamine and midazolam (10 and 0.5 mg/kg respectively; group DM) into the occipital venous sinus. The pharmacokinetic parameters were calculated by HPLC using a non-compartmental modeling. Serial blood samples were collected at baseline and within 15 and 30 min, and 11.5, 2, 4, 8, 12, 24 and 48 h of drug administration. Sedation status over time differed between groups. All animals in group D (8/8; 100%) showed signs of light sedation at t10. Half (4/8; 50%) of these caimans did not progress to deeper levels of sedation. In spite of light sedation at t10, animals in group DM were deeply sedated within 13.13 ± 7.04 min of anesthetic agent injection. The area under the plasma concentration-time curve (AUC0-48) and half-life of dextroketamine changed significantly after combination with midazolam. Even without significant changes in clearance, the almost two-fold increase in the half-life of dextroketamine suggests a slower rate of elimination.

In vitro to in vivo extrapolation to derive a metabolism factor for estimating the aggregate exposure to salicylic acid after dermal exposure of its esters.

As part of the safety assessment of salicylate esters in cosmetics, we developed a metabolism factor based on in vitro to in vivo extrapolation (IVIVE) to provide a better estimation of the aggregate internal exposure to the common metabolite, salicylic acid. Optimal incubation conditions using human liver S9 were identified before measuring salicylic acid formation from 31 substances. Four control substances, not defined as salicylic esters but which could be mistaken as such due to their nomenclature, did not form salicylic acid. For the remaining substances, higher in vitro intrinsic clearance (CLint, in vitro) values generally correlated with lower LogP values. A "High-Throughput Pharmacokinetic" (HTPK) model was used to extrapolate CLint, in vitro values to human in vivo clearance and half-lives. The latter were used to calculate the percentage of substance metabolised to salicylic acid in 24h in vivo following human exposure to the ester, i.e. the "metabolism factor". The IVIVE model correctly reproduced the observed elimination rate of 3 substances using in silico or in vitro input parameters. For other substances, in silico only-based predictions generally resulted in lower metabolism factors than when in vitro values for plasma binding and liver S9 CLint, in vitro were used. Therefore, in vitro data input provides the more conservative metabolism factors compared to those derived using on in silico input. In conclusion, these results indicate that not all substances contribute equally (or at all) to the systemic exposure to salicylic acid. Therefore, we propose a realistic metabolism correction factor by which the potential contribution of salicylate esters to the aggregate consumer exposure to salicylic acid from cosmetic use can be estimated.