Population pharmacokinetics of lisinopril in hypertensive children and adolescents with normal to mildly reduced kidney function.

AIMS: Lisinopril, an angiotensin-converting enzyme inhibitor, is a frequently prescribed antihypertensive drug in the paediatric population, while being used off-label under the age of 6 years in the USA and for all paediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive paediatric patients corresponding with the day-to-day clinical population. METHODS: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05 to 0.2 mg kg-1 . Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2 kg (median 53.2 kg). All data were analysed using Monolix version 2020R1 (Lixoft, France) and R version 3.6.2. RESULTS: A 1-compartment model with first-order absorption and first-order elimination optimally describes the data. Parameter estimates of absorption rate constant (0.075 h-1 [0.062, 0.088], typical value [95% confidence interval]), volume of distribution (31.38 L 70 kg-1 [10.5, 52.3]) and elimination clearance (24.2 L h-1 70 kg-1 [19.5, 28.9]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a linear effect centred around 105 mL min-1  1.73 m-2 . The effects of body weight were implemented using fixed allometric exponents centred around an adult weight of 70 kg. CONCLUSION: Lisinopril dose and regimen adjustments for paediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.

Predictors of augmented renal clearance based on iohexol plasma clearance in critically ill children.

BACKGROUND: Augmented renal clearance (ARC) holds a risk of subtherapeutic drug concentrations. Knowledge of patient-, disease-, and therapy-related factors associated with ARC would allow predicting which patients would benefit from intensified dosing regimens. This study aimed to identify ARC predictors and to describe ARC time-course in critically ill children, using iohexol plasma clearance (CLiohexol) to measure glomerular filtration rate (GFR). METHODS: This is a retrospective analysis of data from the "IOHEXOL" study which validated GFR estimating formulas (eGFR) against CLiohexol. Critically ill children with normal serum creatinine were included, and CLiohexol was performed as soon as possible after pediatric intensive care unit (PICU) admission (CLiohexol1) and repeated (CLiohexol2) after 48-72 h whenever possible. ARC was defined as CLiohexol exceeding normal GFR for age plus two standard deviations. RESULTS: Eighty-five patients were included; 57% were postoperative patients. Median CLiohexol1 was 122 mL/min/1.73 m2 (IQR 75-152). Forty patients (47%) expressed ARC on CLiohexol1. Major surgery other than cardiac surgery and eGFR were found as independent predictors of ARC. An eGFR cut-off value of 99 mL/min/1.73 m2 and 140 mL/min/1.73 m2 was suggested to identify ARC in children under and above 2 years, respectively. ARC showed a tendency to persist on CLiohexol2. CONCLUSIONS: Our findings raise PICU clinician awareness about increased risk for ARC after major surgery and in patients with eGFR above age-specific thresholds. This knowledge enables identification of patients with an ARC risk profile who would potentially benefit from a dose increase at initiation of treatment to avoid underexposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179564, registered retrospectively on January 5, 2022.

Doxycycline pharmacokinetics and tissue depletion in striped catfish (Pagasianodon hypophthalmus) after oral administration.

The pharmacokinetics and residue depletion of doxycycline (DOX) in striped catfish (Pagasianodon hypophthalmus) after oral dosage were investigated. The pharmacokinetic experiment was conducted in an aquarium, while the experiment of residue depletion was performed in both an aquarium and earth ponds. Medicated feed was administered orally using the gavage method at a dosage of 20 mg/kg body weight. Blood, liver, and kidney from medicated fish samples were collected. In the depletion experiments, fish were fed medicated feed for five consecutive days at a dosage of 20 mg/kg body weight, with samples collected during and after medication. The concentrations of DOX were quantified using an LC-MS/MS system. The pharmacokinetics parameters of DOX in striped catfish included the absorption rate constant (ka), absorption half-life (T1/2abs), maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), and area under the plasma concentration-time curve from time 0 to 96 h (AUC0-96 h) which were 0.12 h-1, 5.68 h, 1123.45 ng/mL, 8.19 h, and 25,018 ng/mL/h, respectively. Residue depletion results indicated that the withdrawal times of DOX in muscle (with skin) from fish kept in the aquarium were slightly longer than that in fish raised in earth ponds, corresponding to 194 degree-days compared with 150 degree-days. In conclusion, administration of DOX at the dosage of 20 mg/kg body weight can be used for treatment of bacterial infections in striped catfish, and a withdrawal time of 5 days at 29.4°C will ensure consumer food safety due to the rapid depletion of DOX from muscle and skin.

Widespread triazole pesticide use affects infection dynamics of a global amphibian pathogen.

The sixth mass extinction is a consequence of complex interplay between multiple stressors with negative impact on biodiversity. We here examine the interaction between two globally widespread anthropogenic drivers of amphibian declines: the fungal disease chytridiomycosis and antifungal use in agriculture. Field monitoring of 26 amphibian ponds in an agricultural landscape shows widespread occurrence of triazole fungicides in the water column throughout the amphibian breeding season, together with a negative correlation between early season application of epoxiconazole and the prevalence of chytrid infections in aquatic newts. While triazole concentrations in the ponds remained below those that inhibit growth of Batrachochytrium dendrobatidis, they bioaccumulated in the newts' skin up to tenfold, resulting in cutaneous growth-suppressing concentrations. As such, a concentration of epoxiconazole, 10 times below that needed to inhibit fungal growth, prevented chytrid infection in anuran tadpoles. The widespread presence of triazoles may thus alter chytrid dynamics in agricultural landscapes.

Cefquinome shows a higher impact on the pig gut microbiome and resistome compared to ceftiofur.

Cephalosporins are licensed for treatment of severe bacterial infections in different species. However, the effect of these antimicrobials on the fecal microbiome and potential spread of resistance-associated genes causes great concern. This highlights the need to understand the impact of cephalosporins on the porcine fecal microbiome and resistome. A combination of long-read 16S rRNA gene and shotgun metagenomic sequencing was applied to investigate the effect of conventional treatment with either ceftiofur (3 mg.kg-1 intramuscular, 3 consecutive days) or cefquinome (2 mg.kg-1 intramuscular, 5 consecutive days) on the porcine microbiome and resistome. Fecal samples were collected from 17 pigs (6 ceftiofur treated, 6 cefquinome treated, 5 control pigs) at four different timepoints. Treatment with ceftiofur resulted in an increase in Proteobacteria members on microbiome level, while on resistome level selection in TetQ containing Bacteroides, CfxA6 containing Prevotella and blaTEM-1 containing Escherichia coli was observed. Cefquinome treatment resulted in a decline in overall species richness (α-diversity) and increase in Proteobacteria members. On genus level, administration of cefquinome significantly affected more genera than ceftiofur (18 vs 8). On resistome level, cefquinome resulted in a significant increase of six antimicrobial resistance genes, with no clear correlation with certain genera. For both antimicrobials, the resistome levels returned back to the control levels 21 days post-treatment. Overall, our study provides novel insights on the effect of specific cephalosporins on the porcine gut microbiome and resistome after conventional intramuscular treatment. These results might contribute to better tailoring of the most ideal treatment strategy for some bacterial infections.

Porcine ear necrosis: characterization of lesions and associated pathogens.

Porcine ear necrosis (PEN) is characterized by ulcerative lesions of the ear auricle. To investigate that problem, three farms with PEN in nursery pigs were included, and the study aim was to characterize PEN and the potential role of pathogens and mycotoxins. Within each farm, one batch of weaned piglets was included and the prevalence and severity of PEN were monitored for 6-7 weeks. Within each batch, 30 PEN-affected/non-affected animals were randomly selected. Blood samples were taken from these animals, to assess the systemic presence of pathogens and mycotoxins, as well as punch biopsies from the ear auricle for histopathological examination. From 10 animals, scrapings and swabs from the lesions were subjected to nanopore metagenomic sequencing and bacteriological cultivation, respectively. In all three farms, lesions appeared within 3-4 weeks post-weaning. The prevalence at the end of the nursery was 33%, 24%, and 46% for farms A, B, and C, respectively. Most affected pigs had mild to moderate lesions. Blood samples revealed low to very low levels of pathogens and mycotoxins. Different bacteria such as Staphylococcus, Streptococcus, Fusobacterium, Mycoplasma, and Clostridium species were identified by sequencing in the scrapings. The first two pathogens were also most often identified in bacterial cultures. Mycoplasma hyopharyngis was only found in PEN-affected pigs. Histopathological changes were primarily observed in the outer layer of the epidermis. The results suggest that PEN lesions develop by damage to the outer part of the skin e.g. by ear suckling or biting, followed by multiplication of opportunistic pathogens.

Qualitative risk assessment of homogeneity, stability, and residual concentrations of antimicrobials in medicated feed and drinking water in pig rearing.

BACKGROUND: Despite the common use of oral group treatment in pig rearing, the magnitude of the factors influencing the homogeneity and stability of antimicrobial drugs in medicated feed and medicated drinking water are largely unknown, as well as the residual concentrations of the drugs after the end of the treatment. RESULTS: This study presents a qualitative risk assessment to estimate the magnitude of the risks for reduced homogeneity and stability, and increased residual concentrations of antimicrobial drugs in medicated feed and drinking water on the farm. Risk assessment was done using a questionnaire and farm visits (n = 52), combined with a second questionnaire, and concentrations of amoxicillin and doxycycline measured in medicated feed and water samples, each collected on 10 farms. For medicated feed, the duration of storage in the silo did not show to influence the concentration levels in a consistent trend, while the treatment duration had a low to negligible effect. A moderate to high risk was found caused by human error when preparing the medicated feed on the farm. Purchased medicated feed greatly reduces the risk of human error and drugs remain stable during the duration of treatment, while the risk of residual concentrations after the end of the treatment was estimated to be low to moderate. The feed intake variability was identified as a moderate to high risk factor. For medicated drinking water, the type of dosing pump, age of pre-solution, and human errors during the preparation of the pre-solution present a moderate to high risk on homogeneity and stability. Precipitation of the active substance in the absence of a stirrer in a drinking water tank was shown to be a low to moderate risk factor for residues after treatment. Waterline length had a weak correlation with the concentrations of the antimicrobials, while a moderate to high influence was detected for the water intake by the pigs. CONCLUSIONS: A considerable variation in drug concentration in both medicated feed and medicated drinking water was detected depending on their preparation. Therefore, it is important to know which factors influence the homogeneity and stability, and the residual concentrations after treatment.

No Effect of Acute Balenine Supplementation on Maximal and Submaximal Exercise Performance in Recreational Cyclists.

Carnosine (ß-alanyl-L-histidine) and its methylated analogues anserine and balenine are highly concentrated endogenous dipeptides in mammalian skeletal muscle that are implicated in exercise performance. Balenine has a much better bioavailability and stability in human circulation upon acute ingestion, compared to carnosine and anserine. Therefore, ergogenic effects observed with acute carnosine and anserine supplementation may be even more pronounced with balenine. This study investigated whether acute balenine supplementation improves physical performance in four maximal and submaximal exercise modalities. A total of 20 healthy, active volunteers (14 males; six females) performed cycling sprints, maximal isometric contractions, a 4-km TT and 20-km TT following either preexercise placebo or 10 mg/kg of balenine ingestion. Physical, as well as mental performance, along with acid-base balance and glucose concentration were assessed. Balenine was unable to augment peak power (p = .3553), peak torque (p = .3169), time to complete the 4 km (p = .8566), nor 20 km time trial (p = .2660). None of the performances were correlated with plasma balenine or CN1 enzyme activity. In addition, no effect on pH, bicarbonate, and lactate was observed. Also, the supplement did not affect mental performance. In contrast, glucose remained higher during and after the 20 km time trial following balenine ingestion. In conclusion, these results overall indicate that the functionality of balenine does not fully resemble that of carnosine and anserine, since it was unable to elicit performance improvements with similar and even higher plasma concentrations.

Reliability of glomerular filtration rate estimating formulas compared to iohexol plasma clearance in critically ill children.

Accurate renal function assessment is crucial to guide intensive care decision-making and drug dosing. Estimates of glomerular filtration rate (eGFR) are routinely used in critically ill children; however, these formulas were never evaluated against measured GFR (mGFR) in this population. We aimed to assess the reliability of common eGFR formulas compared to iohexol plasma clearance (CLiohexol) in a pediatric intensive care (PICU) population. Secondary outcomes were the prevalence of acute kidney injury (AKI) (by pRIFLE criteria) and augmented renal clearance (ARC) (defined as standard GFR for age + 2 standard deviations (SD)) within 48 h after admission based on mGFR and eGFR by the revised Schwartz formula and the difference between these two methods to diagnose AKI and ARC. In children, between 0 and 15 years of age, without chronic renal disease, GFR was measured by CLiohexol and estimated using 26 formulas based on creatinine (Scr), cystatine C (CysC), and betatrace protein (BTP), early after PICU admission. eGFR and mGFR results were compared for the entire study population and in subgroups according to age, using Bland-Altman analysis with calculation of bias, precision, and accuracy expressed as percentage of eGFR results within 30% (P30) and 10% (P10) of mGFR. CLiohexol was measured in 98 patients. Mean CLiohexol (± SD) was 115 ± 54 ml/min/1.73m2. Most eGFR formulas showed overestimation of mGFR with large bias and poor precision reflected by wide limits of agreement (LoA). Bias was larger with CysC- and BTP-based formulas compared to Scr-based formulas. In the entire study population, none of the eGFR formulas showed the minimal desired P30 > 75%. The widely used revised Schwartz formula overestimated mGFR with a high percentage bias of - 18 ± 51% (95% confidence interval (CI) - 29; - 9), poor precision with 95% LoA from - 120 to 84% and insufficient accuracy reflected by P30 of only 51% (95% CI 41; 61), and P10 of 21% (95% CI 13; 66) in the overall population. Although performance of Scr-based formulas was worst in children below 1 month of age, exclusion of neonates and younger children did not result in improved agreement and accuracy. Based on mGFR, prevalence of AKI and ARC within 48 h was 17% and 45% of patients, respectively. There was poor agreement between revised Schwartz formula and mGFR to diagnose AKI (kappa value of 0.342, p < 0.001; sensitivity of 30%, 95% CI 5; 20%) and ARC (kappa value of 0.342, p < 0.001; sensitivity of 70%, 95% CI 33; 58). CONCLUSION: In this proof-of-concept study, eGFR formulas were found to be largely inaccurate in the PICU population. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. More research in subgroup populations is warranted to conclude on generalizability of these study findings. CLINICALTRIALS: gov NCT05179564, registered retrospectively on January 5, 2022. WHAT IS KNOWN: • Both acute kidney injury and augmented renal clearance may be present in PICU patients and warrant adaptation of therapy, including drug dosing. • Biomarker-based eGFR formulas are widely used for GFR assessment in critically ill children, although endogenous filtration biomarkers have important limitations in PICU patients and eGFR formulas have never been validated against measured GFR in this population. WHAT IS NEW: • eGFR formulas were found to be largely inaccurate in the PICU population when compared to measured GFR by iohexol clearance. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. • Iohexol plasma clearance could be considered an alternative for accurate GFR assessment in PICU patients.

Perioperative pharmacokinetics and pharmacodynamics of meloxicam in emus (Dromaius novaehollandiae) of different age groups using nonlinear mixed effect modelling.

Meloxicam is a widely used nonsteroidal anti-inflammatory drug in avian species. However, variability in pharmacokinetic (PK) and pharmacodynamic (PD) parameters in birds warrants species-specific studies for dose and dosing interval optimization. We performed a perioperative PK study of meloxicam (0.5 mg/kg, intravenously) on emus of three different age groups: 3 chicks (5 weeks old, 3.5 kg), 4 juveniles (26 weeks old, 18.8 kg) and 6 adults (66 weeks old, 38.8 kg). A two-compartment population PK model including weight as a significant covariate on clearance and central volume of distribution (V1) best fitted the data. The typical values (20 kg bird) for clearance and V1 were 0.54 L/kg/h and 0.095 L/kg. Both parameters significantly decreased with increasing weight/age. Meloxicam potency and selectivity for COX-1 and COX-2 were measured in whole blood assays (TxB2 production endpoint). Meloxicam was partially selective in emus (IC50 COX-1:COX-2 = 9.1:1). At the current empirical dose (0.5 mg/kg/24 hr), plasma meloxicam concentration is above IC50 of COX-2 for only 2 hr. PK/PD predicted dose required for 80% COX-2 inhibition over 24 hr were 3.4, 1.4 and 0.95 L/kg/day in chicks, juveniles and adult emus, respectively. The safety, therapeutic efficacy and practicality of modifying the daily dose or dose interval should be considered for dose recommendations in emus.