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Background Physiologically-based toxicokinetic models in livestock need to account for growth during long-term exposure studies due to increase in tissue volume and subsequent dilution of concentration. Growth of an average individual of a livestock species was modelled through the Richards family of sigmoidal growth curve models. Average weight gain data of multiple breeds stemming from beef and dairy cattle, laying hens, broiler chickens, and sheep were obtained from scientific literature and industry. Growth curves including the four-parameter Richards curve possessing a flexible inflection point and the three-parameter West, Von Bertalanffy, Monomolecular, and Gompertz curves were fitted to pooled and breed-specific species data. Regression weights were applied to counteract heteroscedasticity, and correlation between residuals was modelled. Fits were compared with the Akaike and Bayesian information criteria, the root mean squared error, and likelihood-ratio tests. Physiological plausibility of curve estimates was also considered. Averages of breed weight gain were used, thus random effects pertaining to individuals were not modelled. Results For the pooled fits in beef and dairy cattle, best results were attained by the Von Bertalanffy followed by the West and Richards curves. In laying hen, best fits were attained by the Gompertz curve, followed by the West curve. In male broiler chickens, the Richards curve alone performed best, while in female broiler chickens, the West curve performed similarly well to the Richards curve. For sheep, the Monomolecular curve fitted best. In the breed-specific fits, the Richards curve outperformed the other curve models in all species except laying hens. No statistical difference was found in estimating a breed-specific or a common inflection point of the Richards curve in beef and dairy cattle, provided all other curve parameters were breed-specific. A size-scaled comparison using all animal data showed that the Von Bertalanffy curve returned smallest root mean squared error. Conclusion In the pooled fits, parsimonious curve models such as the West and Von Bertalanffy curves performed similarly to the more flexible Richards curve. The parameter estimates in this study can be used for risk assessment to integrate growth of an individual in a generic physiologically-based toxicokinetic model.

In Europe, the classification systems of the WHO, WOAH (founded as OIE), and EMA are the prevailing standard documents guiding the prudent use of antibiotic substances. While the WHO document “Critically important antimicrobials for human medicine” eponymously focusses on the use in humans, the other two documents, “OIE List of Antimicrobial Agents of Veterinary Importance” and “EMA Categorization of antibiotics for use in animals,” concentrate exclusively on the prudent use of antibiotics in animals. One common purpose of these classification systems is to provide guidance in making sound decisions on the choice of antibiotics for treating humans as well as animals. Although the latest editions of these compendia refer to one another and bear a clear resemblance at the category levels, some of the substances are grouped into unequal classes. This review illustrates the specific perspectives of the three categorization systems under consideration. The arguments raised for different classifications between the WHO and the EMA are exemplified for amoxicillins without beta-lactamase inhibitors, macrolides, sulfonamides, and colistin. For the daily clinical use of antibiotics, veterinarians should consider the EMA document, and, under tentative circumstances, consult the OIE list.

Dried blood spot (DBS) sampling has emerged as a promising microsampling technique in biomedical and clinical research, offering advantages such as reduced invasiveness, minimal blood volume requirements, and enhanced analyte stability. Although well established in human medicine for neonatal screening and diagnostic applications, its potential in veterinary pharmacology remains underexplored. This study investigated the feasibility of using DBS samples to quantify anesthetic agents—ketamine and medetomidine in cats and lidocaine in horses—during routine surgical procedures at a veterinary teaching hospital. A standardized DBS collection protocol was developed, and LC-MS/MS methods were validated for the quantification of target analytes in both DBS and plasma samples. These methods were subsequently applied to real samples collected during anesthesia to conduct pharmacokinetic analyses. Comparative evaluations, including Bland–Altman analysis, assessed the suitability of DBS samples for pharmacokinetic studies in veterinary medicine. Preliminary results indicated satisfactory agreement for medetomidine, meeting EMA guidelines, with 75.6% of mean values falling within ±20% of paired measurements. Results for ketamine (46.9%) were promising but require further optimization, while those for lidocaine (21.4%) highlighted the need for additional investigation. These findings underscore the potential of DBS sampling as a minimally invasive alternative for pharmacokinetic studies in veterinary medicine, particularly for medetomidine, while identifying areas for further methodological refinement. Future research should optimize DBS techniques and expand their application to other drugs and species, broadening their impact on veterinary pharmacology.

Acquired macrolide resistance is poorly studied in Escherichia coli because of intrinsic resistance and limited antimicrobial activity in Gram-negative bacteria. This study reveals new information on the prevalence and distribution of macrolide resistance determinants in a comprehensive collection of porcine clinical E. coli from Denmark. Escherichia coli is intrinsically resistant to macrolides due to outer membrane impermeability, but may also acquire macrolide resistance genes by horizontal transfer. We evaluated the prevalence and types of acquired macrolide resistance determinants in pig clinical E. coli , and we assessed the ability of peptidomimetics to potentiate different macrolide subclasses against strains resistant to neomycin, a first-line antibiotic in the treatment of pig-enteric infections. The erythromycin MIC distribution was determined in 324 pig clinical E. coli isolates, and 62 neomycin-resistant isolates were further characterized by genome sequencing and MIC testing of azithromycin, spiramycin, tilmicosin, and tylosin. The impact on potency achieved by combining these macrolides with three selected peptidomimetic compounds was determined by checkerboard assays in six strains representing different genetic lineages and macrolide resistance gene profiles. Erythromycin MICs ranged from 16 to >1,024 μg/mL. Azithromycin showed the highest potency in wild-type strains (1 to 8 μg/mL), followed by erythromycin (16 to 128 μg/mL), tilmicosin (32 to 256 μg/mL), and spiramycin (128 to 256 μg/mL). Isolates with elevated MIC mainly carried erm (B), either alone or in combination with other acquired macrolide resistance genes, including erm (42), mef (C), mph (A), mph (B), and mph (G). All peptidomimetic-macrolide combinations exhibited synergy (fractional inhibitory concentration index [FICI] < 0.5) with a 4- to 32-fold decrease in the MICs of macrolides. Interestingly, the MICs of tilmicosin in wild-type strains were reduced to concentrations (4 to 16 μg/mL) that can be achieved in the pig intestinal tract after oral administration, indicating that peptidomimetics can potentially be employed for repurposing tilmicosin in the management of E. coli enteritis in pigs. IMPORTANCE Acquired macrolide resistance is poorly studied in Escherichia coli because of intrinsic resistance and limited antimicrobial activity in Gram-negative bacteria. This study reveals new information on the prevalence and distribution of macrolide resistance determinants in a comprehensive collection of porcine clinical E. coli from Denmark. Our results contribute to understanding the correlation between genotypic and phenotypic macrolide resistance in E. coli . From a clinical standpoint, our study provides an initial proof of concept that peptidomimetics can resensitize E. coli to macrolide concentrations that may be achieved in the pig intestinal tract after oral administration. The latter result has implications for animal health and potential applications in veterinary antimicrobial drug development in view of the high rates of antimicrobial-resistant E. coli isolated from enteric infections in pigs and the lack of viable alternatives for treating these infections.

The effect of age dependent pharmacokinetics (PK) on the clinical efficacy of oxytetracycline (OTC) against Bovine Respiratory Disease (BRD) in beef cattle was studied, using a Physiologically Based Pharmacokinetic (PBPK) model. The model includes a bodyweight dependent renal clearance. To mimic/reproduce the long terminal half-live a bone forming tissue compartment was considered. Data for the development, calibration and validation of the model were obtained from public literature. To integrate the PK with the pharmacodynamics (PD) of OTC, Monte Carlo simulations were performed using this PBPK model to predict time-concentration curves for two commonly used dosing regimens of short-acting and long-acting injectable OTC formulations in virtual populations of 5,000 steer calves of 100 kg and 400 kg. These curves were then used to calculate the value of the PKPD index for OTC, which is the ratio of the area under the concentration-time curve for 24 h (AUC 24h ) over the minimum inhibitory concentration (MIC) of the target pathogen (AUC 24h /MIC). The MIC values were for Mannheimia haemolytica , the dose-limiting pathogen for BRD. This integration of PBPK and PD for OTC used for the treatment of BRD in calves indicated that the Probability of Target Attainment (PTA) was sufficient for efficacy in calves of 400 kg, but insufficient for calves of 100 kg, when using a long acting dosing regimen of 20 mg/kg BW, twice, with a 48-h interval. The use of a dosing regimen of 10 mg/kg BW/day for 4 days predicted sufficient PTAs in both age groups.

Selection and spread of Extended Spectrum Beta-Lactamase (ESBL) -producing Enterobacteriaceae within animal production systems and potential spillover to humans is a major concern. Intramammary treatment of dairy cows with first-generation cephalosporins is a common practice and potentially selects for ESBL-producing Enterobacteriaceae , although it is unknown whether this really occurs in the bovine fecal environment. We aimed to study the potential effects of intramammary application of cephapirin (CP) and cefalonium (CL) to select for ESBL-producing Escherichia coli in the intestinal content of treated dairy cows and in manure slurry, using in vitro competition experiments with ESBL and non-ESBL E. coli isolates. No selection of ESBL-producing E. coli was observed at or below concentrations of 0.8 µg/ml and 4.0 µg/ml in bovine feces for CP and CL, respectively, and at or below 8.0 µg/ml and 4.0 µg/ml, respectively, in manure slurry. We calculated that the maximum concentration of CP and CL after intramammary treatment with commercial products will not exceed 0.29 µg/ml in feces and 0.03 µg/ml in manure slurry. Therefore, the results of this study did not find evidence supporting the selection of ESBL-producing E. coli in bovine feces or in manure slurry after intramammary use of commercial CP or CL-containing products.

Pediatric drug development, especially in disease areas that only affect children, can be stimulated by using juvenile animal models not only for general safety studies, but also to gain knowledge on the pharmacokinetic and pharmacodynamic properties of the drug. Recently, the conventional growing piglet has been suggested as juvenile animal model. However, more studies with different classes of drugs are warranted to make a thorough evaluation whether the juvenile pig might be a suitable preclinical animal model. Ibuprofen is one of the most widely used non-steroidal anti-inflammatory drugs in human. The present study determined the PK parameters, gastro-intestinal and renal safety of 5 mg/kg BW ibuprofen after single intravenous, single oral and multiple oral administration to each time eight pigs (four males, four females) aging 1, 4, 8 weeks and 6-7 months. Oral administration was performed via a gastrostomy button. A jugular catheter was used for intravenous administration and blood sampling. To assess NSAID induced renal toxicity, renal function was evaluated using iohexol and -aminohippuric acid as markers for glomerular filtration rate and renal plasma flow, respectively. After the trial, necropsy and histology was performed to evaluate macroscopic and microscopic gastro-intestinal as well as renal lesions. Both enantiomers, R-ibuprofen and S-ibuprofen, were determined in plasma using an in-house developed and validated UHPLC-MS/MS method. Pharmacokinetic parameters were estimated using compartmental analysis. Clearance and volume of distribution of total ibuprofen and both enantiomers increased with age as was observed in human. The rate of stereochemical conversion decreased with age. Multiple oral dosing decreased the absolute oral bioavailability and maximum plasma concentration of R-ibuprofen and food consumption did not influence drug absorption. Based on the limited available pediatric literature, the current study might suggest the conventional pig as suitable animal model to evaluate NSAIDs for pediatric use.

Glucocorticoids such as prednisolone are commonly used in dogs but there is sparse quantitative pharmacokinetic and pharmacodynamic information of this drug in this species. The objective of this study was to quantitatively characterize the concentration-effect relationship for prednisolone in dogs on neutrophil and lymphocyte trafficking and cortisol suppression. Nine beagles, 2–12 years old and part of a group for teaching/research were used in a 4-way crossover experiment including two treatments, active or placebo, administered either per os (PO) or intravenously (IV). Plasma was analyzed for prednisolone and cortisol using ultra-high performance liquid chromatography – tandem mass spectrometry. Leucocyte counts were performed in whole blood. Data was then analyzed by non-linear mixed effect modeling to estimate pharmacokinetic and pharmacodynamic parameters. After administration of prednisolone sodium succinate IV, the typical value (between subject variation) for total body prednisolone clearance was 1,370 ml/h·kg (13.4%). The volumes of the central and peripheral compartment were 2,300 ml/kg (10.7%) and 600 ml/kg (16.0%), respectively. The terminal plasma half-life was 1.7 h. The prednisolone plasma concentration producing 50% of the maximum response was 10 ng/mL (90.3%), 22.5 ng/ml (52.3%) and 0.04 ng/mL (197.3%) for neutrophil, lymphocyte and cortisol response, respectively. The administered dose (1 mg/kg) increased neutrophil and decreased lymphocyte numbers but not over the entire dosage interval of 24 h, due to the short half-life. However, glucocorticoids have a wide range of responses. An anti-inflammatory response due to altered gene transcription might have a longer duration. Future studies on the anti-inflammatory potency together with data presented are needed to optimize future dosage recommendations in dogs.

Background: The activation of the growth hormone receptor (GHR) is a major determinant of body growth. Defective GHR signaling, as seen in human Laron dwarfism, resulted in low plasma IGF-1 concentrations and limited growth, but also marked absence in the development of breast cancer and type 2 diabetes. In vitro, we identified a small molecule (C#1) that inhibits the translation of GHR mRNA to receptor protein. Methods: Before its application in humans as a potential anticancer drug, C#1 was tested in animals to evaluate whether it could be administered to achieve a plasma concentration in vivo that inhibits cell proliferation in vitro without causing unwanted toxicity. To evaluate the efficacy and toxicity of C#1, a group of six intact female Beagle dogs was treated daily each morning for 90 days with an oral solution of C#1 in Soiae oleum emulgatum at a dose of 0.1 mg/kg body weight. During treatment, dogs were closely monitored clinically, and blood samples were taken to measure plasma C#1 concentrations, complete blood counts (CBC), clinical chemistry, and endocrinology. At the end of the treatment, dogs were euthanized for gross and histopathological analysis. An additional group of six female Beagle dogs was included for statistical reasons and only evaluated for efficacy during treatment for 30 days. Results: Daily administration of C#1 resulted in a constant mean plasma concentration of approximately 50 nmol/L. In both groups, two out of six dogs developed decreased appetite and food refusal after 4–5 weeks, and occasionally diarrhea. No significant effects in CBC or routine clinical chemistry were seen. Plasma IGF-1 concentrations, used as biomarkers for defective GHR signaling, significantly decreased by 31% over time. As plasma growth hormone (GH) concentrations decreased by 51% as well, no proof of GHR dysfunction could be established. The measured 43% decrease in plasma acylated/non-acylated ghrelin ratios will also lower plasma GH concentrations by reducing activation of the GH secretagogue receptor (GHSR). C#1 did not directly inhibit the GHSR in vivo, as shown in vitro. There were no significant effects on glucose, lipid, or folate/homocysteine metabolism. Conclusions: It is concluded that with daily dosing of 0.1 mg C#1/kg body weight, the induction of toxic effects prevented further increases in dosage. Due to the concomitant decrease in both IGF-1 and GH, in vivo inhibition of GHR could not be confirmed. Since the concept of specific inhibition of GHR synthesis by small molecules remains a promising strategy, searching for compounds similar to C#1 with lower toxicity should be worthwhile.

Background Septicaemia in the neonatal foal is caused by both Gram positive and Gram negative bacteria. The life‐threatening nature of this condition requires treatment to be initiated with broad spectrum antimicrobial drugs pending antimicrobial susceptibility testing. Potentiated sulphonamides, for example, trimethoprim combined with sulfadiazine, could be clinically relevant options but their pharmacokinetics in the neonatal foal are unknown. Objectives To describe the plasma disposition of trimethoprim and sulfadiazine in neonatal foals and to relate the results to patterns in the minimum inhibitory concentration (MIC) for Escherichia coli, a recognized pathogen in neonatal foal sepsis. Method A total of five doses of trimethoprim (2.5 mg/kg) and sulfadiazine (12.5 mg/kg) were administered intravenously every 12 h to eight neonatal foals that were 3 days old at inclusion. A non‐linear mixed effects model was fitted to the trimethoprim and sulfadiazine experimental data. The 24 h area under the free plasma trimethoprim and sulfadiazine concentration‐time curves (fAUC) and the pharmacokinetic/pharmacodynamik (PK/PD)‐index fAUC/MIC was calculated to evaluate the potential clinical benefits of the administered dose. Results For trimethoprim, the typical values were 1.99 L/kg, 0.33 L/h·kg and 4.2 h for the apparent volume of distribution, clearance and terminal half‐life, respectively. The 24 h fAUC for trimethoprim was 11.3 μg·h/ml (7.2–15.2) and the fAUC/MIC ratio for E. coli was 23 (16.4–29.2) (population mean (range)). For sulfadiazine, the typical values were 0.61 L/kg, 0.09 L/h·kg and 5.3 h for the apparent volume of distribution, clearance and terminal half‐life, respectively. The 24 h fAUC for sulfadiazine was 246.8 μg·h/ml (175.6–335.4). Conclusion For trimethoprim, the plasma exposure is insufficient in some foals to successfully treat bacterial infections with an MIC‐value of 0.5 μg/ml using the studied dosing regimen. Septicaemia is a serious condition in the neonatal foal but till date the pharmacokinetics of a trimethoprim and sulfadiazine combination has not been evaluated. To assure therapeutic effect and decrease antimicrobial resistance this information is warranted.