Pollutant exposure and myocardial injury: Protocol and progress report for a toxicological systematic mapping review.

An increasing body of evidence identifies pollutant exposure as a risk factor for cardiovascular disease (CVD), while CVD incidence rises steadily with the aging population. Although numerous experimental studies are now available, the mechanisms through which lifetime exposure to environmental pollutants can result in CVD are not fully understood. To comprehensively describe and understand the pathways through which pollutant exposure leads to cardiotoxicity, a systematic mapping review of the available toxicological evidence is needed. This protocol outlines a step-by-step framework for conducting this review. Using the National Toxicology Program (NTP) Health Assessment and Translation (HAT) approach for conducting toxicological systematic reviews, we selected 362 out of 8111 in vitro (17%), in vivo (67%), and combined (16%) studies for 129 potential cardiotoxic environmental pollutants, including heavy metals (29%), air pollutants (16%), pesticides (27%), and other chemicals (28%). The internal validity of included studies is being assessed with HAT and SYRCLE Risk of Bias tools. Tabular templates are being used to extract key study elements regarding study setup, methodology, techniques, and (qualitative and quantitative) outcomes. Subsequent synthesis will consist of an explorative meta-analysis of possible pollutant-related cardiotoxicity. Evidence maps and interactive knowledge graphs will illustrate evidence streams, cardiotoxic effects and associated quality of evidence, helping researchers and regulators to efficiently identify pollutants of interest. The evidence will be integrated in novel Adverse Outcome Pathways to facilitate regulatory acceptance of non-animal methods for cardiotoxicity testing. The current article describes the progress of the steps made in the systematic mapping review process.

Heart disease is a leading global cause of death. Recent research indicates that certain environmental chemicals can worsen heart problems. We're conducting a rigorous review of scientific studies to understand how these chemicals affect the heart. This will inform policymakers and promote non-animal testing methods for cardiotoxicity by providing a clear overview of the toxicological evidence. We have reviewed over 8,000 articles and focused on 362 studies about 129 chemicals, including heavy metals, air pollutants and pesticides, and their effects on the heart. The current manuscript describes the used methods and steps made in this process. The outcome of our systematic review of these 362 articles will be a comprehensive database that will aid the development of alternative testing methods for cardiotoxicity.

PHARMACOKINETICS OF ORAL FLUNIXIN MEGLUMINE, MELOXICAM, OR GABAPENTIN IN THREE BLACK RHINOCEROS (DICEROS BICORNIS).

Pharmacokinetics of single, separate doses of IV flunixin meglumine (1 mg/kg), IV meloxicam (0.5 mg/kg), oral flunixin meglumine (1 mg/kg), oral meloxicam (1 mg/kg), and oral gabapentin (15 mg/kg) in three adult black rhinoceroses (Diceros bicornis) were determined from serial blood collection made over 72 h. The concentration versus time profiles were analyzed for each drug and route in each individual rhinoceros, and individual pharmacokinetic parameters were calculated for each medication administered. Meloxicam had near complete bioavailability in each trial, while flunixin meglumine was generally lower. Oral meloxicam was noted with similar half-life values between all animals (range 9.22-14.52 h) tested, while oral gabapentin had a larger range (range 10.25-24.85 h). Oral flunixin meglumine achieved a lower Cmax (range 170.67-664.38 ng/ml) in this study compared with the mean Cmax (1,207 ng/ml) reported in a similar study in white rhinoceroses (Ceratotherium simum), but some overlap in range of values was noted. Oral flunixin meglumine Tmax (range 1.05-10.78 h) and half-life (range 3.88-14.85 h) values in black rhinoceroses was similar to mean values reported in white rhinoceroses (3 and 8.3 h, respectively).

European regulations on the use of antibiotics in veterinary medicine.

Antimicrobial resistance endangers the successful combat of bacterial infections in humans and animals. The common use of antibiotic classes including those of high clinical value in human as well as veterinary medicine is a critical factor contributing to or suspected to promote the emergence of antibiotic resistance. New legal provisions laid down in veterinary drug legislations and related guidelines and advice are in force in the European Union to safeguard the effectiveness, accessibility and availability of antibiotics. Categorisation of antibiotics in classes of importance for treatment of infections of humans by the WHO was one of the first steps. This task is also undertaken for antibiotics for treatment of animals by the EMA's Antimicrobial Advice Ad Hoc Expert Group. The new veterinary Regulation (EU) 2019/6 has extended restrictions for use of some antibiotics in animals to a full ban of certain antibiotics. While some (but not all) antibiotic compounds not being authorized in veterinary medicine may still be used in companion animals more strict provisions were already applicable for treatment of food producing animal species. Distinct regulations are in place for the treatment of animals kept in large numbers in flocks. Initial regulations focussed on the protection of consumers from residues of veterinary drugs in food commodities, new regulations address prudent (not routinely) and responsible selection, prescription and use of antibiotics, and have improved the practicality for cascade use outside the terms of marketing authorisation. Mandatory recording of use of veterinary medicinal products for food safety reasons is extended to rules for veterinarians and owners or holders of animals to regularly report the use of antibiotics for the purpose of official surveillance of consumption. National sales data of antibiotic veterinary medicinal products have been collected on a voluntary basis until 2022 by ESVAC, which has created awareness of major differences between EU member states. A significant decline in sales was reported for third and fourth generation cephalosporines, polymyxins (colistin), and (fluoro)quinolones since the initiation in 2011.

Understanding the background and clinical significance of the WHO, WOAH, and EMA classifications of antimicrobials to mitigate antimicrobial resistance.

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.

Systematic review of physiologically based kinetic lactation models for transfer of xenobiotic compounds to milk.

Lactational elimination has been described mathematically for nearly 50 years. Over 40 published articles, containing >50 physiologically based kinetic (PBK) lactation models were included in the systematic review. These PBK models described the lactational elimination of xenobiotic compounds in humans, rats, mice, and dairy cows and goats. A total of 78 compounds have been modelled, ranging from industrial chemicals, pesticides, to pain medication, antibiotics, and caffeine. Few models included several species or compounds, and models were thus generally not translational or generic. Three dairy cow models mechanistically described the intramammary disposition of pharmaceuticals after intramammary administration, including volume changes caused by milking, while empirically describing the remaining pharmacokinetics. The remaining models were semi- or whole body PBK models, describing long-term exposure of environmental pollutants, or short-term exposure of pharmaceuticals. The absolute majority described the disposition to the mammary gland or milk with perfusion limited compartments, but permeability limited models were available as well. With long-term exposure, models often included changes in milk volume and/or consumption by the offspring, and changes in body weight of offspring. Periodic emptying of the mammary gland, as with feeding or milking, was sparsely applied. Rodent models used similar physiological parameters, while values of physiological parameters applied in human models could range widely. When milk composition was included in the models, it most often included the fat content. The review gives an extensive overview of the applied functions and modelling strategies of PBK lactation models.

Potential of ESBL-producing Escherichia coli selection in bovine feces after intramammary administration of first generation cephalosporins using in vitro experiments.

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.

The efficacy of subcutaneous slow-release melatonin implants in the prevention of canine flank alopecia recurrence is uncertain: A double-blind, randomized, placebo-controlled study.

BACKGROUND: Canine flank alopecia (CFA) is characterized by seasonally recurring noninflammatory, occasionally hyperpigmented alopecia predominantly in the thoracolumbar area. Previous studies suggest that reduced production of endogenous melatonin may play a role in the pathogenesis of this condition, and placebo-controlled studies on the efficacy of preventative melatonin treatment are lacking. OBJECTIVE: To evaluate the efficacy of subcutaneous slow-release melatonin implants in the prevention of CFA recurrence. ANIMALS: Twenty-one client-owned dogs with a history of CFA were included in the study. MATERIALS AND METHODS: At time (T)0, a general physical and dermatological examination was performed on each dog, blood was collected for serum biochemistry analysis and two skin biopsies were taken from alopecic areas on the nonsedated affected dogs after subcutaneous injection with 2% lidocaine. Dogs with normal blood work and histological results compatible with CFA were included in the study. Participating dogs were randomly assigned to receive either placebo or 18 mg melatonin subcutaneously in the interscapular area, approximately 2 months before expected CFA onset (T1). CFA recurrence was scored qualitatively as complete, ≤50% recurrence, or no recurrence at 5 and 7 months after the intervention (T2 and T3, respectively). RESULTS: At T3, in dogs treated with placebo (nine of 17), the percentages for complete recurrence, ≤50% recurrence and no recurrence were 44%, 0% and 56%, respectively. In dogs treated with melatonin (eight of 17), these percentages were 25%, 50% and 25%, respectively. There were no statistically significant differences in the scores between melatonin-treated dogs and placebo-treated dogs (p = 0.40). In three of eight melatonin-treated dogs, mild transient swelling was observed at the injection site. CONCLUSIONS: This study did not provide evidence that an 18 mg melatonin implant treatment, although well-tolerated, is efficacious in preventing recurrence of CFA in affected dogs.

Macrolide Resistance and In Vitro Potentiation by Peptidomimetics in Porcine Clinical Escherichia coli.

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.

Plasma atropine concentrations associated with decreased intestinal motility in horses.

Introduction: Atropine is an essential part of the treatment protocol for equine uveitis. Topical atropine administration has been associated with decreased intestinal motility and abdominal pain in horses. Experimental studies have indicated that frequent dosing is associated with a higher risk than dosing every 6 h. Unfortunately, no quantitative pharmacodynamic data for inhibition of the equine gut are published. Materials and methods: Eight standardbred horses were assigned to receive either atropine or saline (control) to be infused over 30 min in a two-treatment cross-over design. Atropine concentrations in plasma were measured using ultra-high-performance liquid chromatography-tandem mass spectrometry. Intestinal motility was measured using borborygmi frequency and electrointestinography (EIG). Experimental data were analyzed using a non-linear mixed effects model. The model was then used to simulate different dosing regimens. Results: Atropine significantly decreased borborygmi response and EIG response. Six horses developed clinical signs of abdominal pain. The pharmacokinetic typical values were 0.31, 1.38, 0.69, and 1.95 L/kg·h for the volumes of the central, the highly perfused, the scarcely perfused compartments, and the total body clearance, respectively. The pharmacodynamic typical values were 0.31 µg/L and 0.6 and 207 nV27 cpm for the plasma concentration at 50% of the maximum response and the maximum response and the baseline of cecal EIG response, respectively. Six different dosing regimens of topical atropine sulfate to the eye (0.4 and 1 mg every hour, every 3 h, and every 6 h) were simulated. Conclusion: The IV PK/PD data coupled with simulations predict that administration of 1 mg of topical atropine sulfate administered to the eye every hour or every 3 h will lead to atropine accumulation in plasma and decreased intestinal myoelectric activity. Administration every 6 h predicted a safe dosing regimen in full-sized horses. Clinical studies would be valuable to confirm the conclusions. For smaller equids and horses put at risk for colic due to othercauses, droplet bottles that deliver 40 µl of 1% atropine sulfate per drop or less may be used to lower the risk further.

A physiologically based pharmacokinetic (PBPK) model exploring the blood-milk barrier in lactating species - A case study with oxytetracycline administered to dairy cows and goats.

Antibiotic excretion into milk depends on several factors such as the compound's physicochemical properties, the animal physiology, and the milk composition. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model describing the passage of drugs into the milk of lactating species. The udder is described as a permeability limited compartment, divided into vascular, extracellular water (EW), intracellular water (IW) and milk, which was stored in alveolar and cistern compartments. The pH and ionization in each compartment and the binding to IW components and to milk fat, casein, whey protein, calcium, and magnesium were considered. Bidirectional passive diffusion across the blood-milk barrier was implemented, based on in vitro permeability studies. The model application used to predict the distribution of oxytetracycline in cow and goat milk, after different doses and routes of administration, was successful. By integrating inter-individual variability and uncertainty, the model also allowed a suitable estimation of the withdrawal periods. Further work is in progress to evaluate the predictive ability of the PBPK model for compounds with different physico-chemical properties that are potentially actively transported in order to extrapolate the excretion of xenobiotics in milk of various animal species including humans.

The disposition of trimethoprim and sulfadiazine in neonatal foals after intravenous administration.

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.

Penetration of topically administered dexamethasone disodium phosphate and prednisolone acetate into the normal equine ocular fluids.

BACKGROUND: Topical dexamethasone and prednisolone are currently the mainstay treatment for equine ophthalmic inflammatory diseases, such as equine recurrent uveitis. Comparative pharmacokinetic studies in horses are lacking and current guidelines are mainly based on empirical data and extrapolation from other species. OBJECTIVES: To investigate the penetration and local concentrations of topically applied dexamethasone and prednisolone in normal equine ocular fluids and serum. STUDY DESIGN: Prospective randomised experimental pharmacokinetic study. METHODS: Twenty-one Shetland ponies without ophthalmic disease were treated bilaterally topically every 2 hours during 24 hours to obtain steady state drug concentrations. One eye was treated with 0.15 mg of dexamethasone disodium phosphate (0.1%), and the other eye was simultaneously treated with 1.5 mg of prednisolone acetate (1%). Serum samples were taken prior to the induction of general anaesthesia. Aqueous and vitreous humour samples were taken during euthanasia at time points after administration of the last dose (t = 5 min, t = 15 min, t = 30 min, t = 60 min, t = 90 min, t = 120 min, t = 180 min). Each pony was randomly assigned to one time point, and three ponies were sampled per time point. Dexamethasone and prednisolone concentrations were measured by liquid chromatography-mass spectrometry. RESULTS: The mean dexamethasone concentration in aqueous humour was 32.4 ng/mL (standard deviation [SD] 10.9) and the mean prednisolone concentration was 321.6 ng/mL (SD 96.0). In the vitreous and in serum samples concentrations of both corticosteroids were below the limit of detection (LOD 2.5 ng/mL). MAIN LIMITATIONS: The study group was limited to subjects without evidence of current ophthalmic disease. A limited number of time points were measured. CONCLUSIONS: Potentially effective dexamethasone and prednisolone concentrations were measured in the anterior chamber, but vitreal concentrations were negligible. Systemic uptake was low. Therefore, treatment with only topically administered corticosteroids is deemed insufficient in horses in cases of posterior uveitis. Further studies evaluating other routes of administration are warranted.

Co-formulation of ketoprofen with tulathromycin alters pharmacokinetic and pharmacodynamic profile of ketoprofen in cattle.

The current studies aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profile and to establish a PK-PD model for ketoprofen in a new fixed combination product containing tulathromycin (2.5 mg/kg) and ketoprofen (3 mg/kg) to treat bovine respiratory disease associated with pyrexia in cattle. Firstly, the effect of different ketoprofen doses as mono-substance (1, 3, and 6 mg/kg subcutaneous) on lipopolysaccharide-induced fever was evaluated which indicated that rectal temperature reduction lasted longer in the calves receiving 3 and 6 mg/kg ketoprofen. Secondly, the PK profile of the combination product was compared with mono-substance products (3 mg/kg subcutaneous and intramuscular). The PK profile of ketoprofen in the combination product was characterized by longer t1/2 , lower Cmax and increased AUC in comparison with mono-substance products. Due to prolonged ketoprofen exposure in the combination product, the pyrexia reducing effect of the combination product lasted longer in a second lipopolysaccharide challenge study in comparison with mono-substance products. Finally, a PK-PD model for the anti-pyretic effect of ketoprofen was developed based on the data from the different studies. The PK-PD model eliminated the need for additional animal experiments and indicated that a 3 mg/kg ketoprofen dose in the combination product provided optimal efficacy.

Induction of gut leakage in young broiler chickens fed a diet with low rye inclusion.

The aim of the present study was to assess the absence of a non-starch polysaccharide (NSP) enzyme in a broiler diet containing a low level (10%) of rye inclusion. Two experimental groups with 40 Ross broilers each, were fed a diet containing 10% rye. One group was supplemented with a NSP enzyme, and the other was not supplemented with the enzyme to increase intestinal viscosity. The birds were fed the respective diets for 14 or 28 days. Intestinal sections were submitted to morphological, morphometric and mRNA-level gene expression analyses. To assess gut leakage, 150 min before euthanasia, broilers had no access to feed and received an oral gavage with fluorescein isothiocyanate-labelled dextran (FITC-d). Serum levels of FITC-d, D-lactate, tight-junction-associated protein 1 (TJAP1), citrulline and ovotransferrin were determined. A significant increase in FITC-d levels was observed in the 14-day-old birds fed the non-supplemented rye diet, and no other serum markers were affected. These birds presented a decreased villus height/crypt depth (VH:CD) ratio and an increased degree of damage in the jejunum. The ileum VH:CD increased, and the goblet cell number decreased in 28-day-old birds fed the non-supplemented rye diet. When broilers were fed the non-supplemented rye diet, the mRNA expression of the tight-junction zona occludens 1 (ZO1) was significantly decreased in the jejunum of 14-day-old broilers, whereas a significant decrease in jejunum mRNA expression of ZO2 and mucin-2 (MUC2) was observed in the jejunum of 28-day-old broilers. In contrast, a significant increase in the mRNA expression of ZO2 was observed in the ileum from 28-day-old broilers fed the non-supplemented rye diet. In conclusion, a 10% rye diet causes intestinal stress in young broiler chickens when the feed is not supplemented with a NSP enzyme. This study may be applied as experimental model of mild gut leakage of broiler chickens.

Pharmacokinetics and bioavailability of ketoprofen when compounded with iron dextran for use in nursing piglets.

In Canada, piglets receive analgesia to control pain after surgical castration. There is interest in examining the potential to mix non-steroidal anti-inflammatory drugs with iron dextran prior to injection to minimize piglet handling and labor. The objective of this study was to compare pharmacokinetics and the relative bioavailability of ketoprofen given alone (3.0 mg/kg IM) versus the same dose of ketoprofen mixed with iron dextran (52.8 mg/kg IM) (ketoprofen + iron dextran) before injection in piglets. Piglets 8 to 11 d old were allocated into 2 treatment groups (n = 8/group). Plasma drug concentrations were measured using mass spectrometry at 13 time points after injection. No significant differences were detected between the 2 groups when examining pharmacokinetic parameters (e.g., Cmax, Tmax, AUC) or relative bioavailability for either S- or R-ketoprofen enantiomers (P > 0.05). However, pain control efficacy and food safety studies of these formulations are required to further examine this practice.

Pharmacocinétique et biodisponibilité du kétoprofène lorsque mélangé avec du fer dextran pour utilisation chez les porcelets allaitants. Au Canada, les porcelets reçoivent une analgésie pour diminuer la douleur après une castration chirurgicale. Il y a un intérêt à examiner la possibilité de mélanger des anti-inflammatoires non stéroïdiens avec du fer dextran avant l'injection afin de minimiser la manipulation des porcelets et le travail. L'objectif de cette étude était de comparer la pharmacocinétique et la biodisponibilité relative du kétoprofène administré seul (3,0 mg/kg IM) par rapport à la même dose de kétoprofène mélangé à du fer dextran (52,8 mg/kg IM) (kétoprofène + fer dextran) avant l'injection des porcelets. Des porcelets âgés de 8 à 11 jours ont été répartis en deux groupes de traitement (n = 8/groupe). Les concentrations plasmatiques de médicament ont été mesurées par spectrométrie de masse à 13 moments dans le temps après l'injection. Aucune différence significative n'a été détectée entre les deux groupes lors de l'examen des paramètres pharmacocinétiques (par ex., Cmax, Tmax, AUC) ou de la biodisponibilité relative pour les énantiomères S- ou R-kétoprofène (P > 0,05). Cependant, des études sur l'efficacité de la diminution de la douleur et la sécurité alimentaire de ces formulations sont nécessaires pour examiner de manière plus approfondie cette pratique.(Traduit par Dr Serge Messier).

Unmitigated Surgical Castration in Calves of Different Ages: Cortisol Concentrations, Heart Rate Variability, and Infrared Thermography Findings.

The objective was to characterize physiological responses to unmitigated surgical castration in calves of varying ages. Thirty male Holstein calves of three ages [<6 w (6W); 3 m (3M); 6 m (6M); n = 10] underwent a simulated castration treatment (SHAM) followed 24 h later by castration (CAST). For both treatments, heart rate variability, eye temperature, and cortisol were measured over time from treatment to specified end points to capture the acute response period. Interactions between treatment and age (p = 0.035) and time and age (p < 0.001) were noted for cortisol. The 6W calves had lower cortisol compared to 6M calves at SHAM and CAST. Cortisol of 6W calves decreased from peak to pre-treatment levels faster than 6M calves. An interaction between time and age was reported in squared differences of inter-beat-intervals (RMSSD; p = 0.02) and high-frequency power (HFP; p = 0.05), whereby both responses decreased in 6W calves during the sampling period which was not seen in 3M and 6M calves. Average eye temperature (AET) differed by age (p = 0.0018) whereby 6W calves had lower AET than 6M calves (p = 0.0013) regardless of treatment and time. The findings suggest that responses to unmitigated surgical castration seem to be mediated by the autonomic nervous system in an age-related manner.

Corrigendum: Comparative Pharmacokinetics of Meloxicam Between Healthy Post-partum vs. Mid-lactation Dairy Cattle.

[This corrects the article DOI: 10.3389/fvets.2020.00548.].

Prednisolone in Dogs-Plasma Exposure and White Blood Cell Response.

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.

Susceptibility of Broiler Chickens to Deoxynivalenol Exposure via Artificial or Natural Dietary Contamination.

Multi-mycotoxin contamination of poultry diets is a recurrent problem, even if the mycotoxins levels are below EU recommendations. Deoxynivalenol (DON) is one of the main studied mycotoxins due to its risks to animal production and health. When evaluating the effects of DON, one must consider that under practical conditions diets will not be contaminated solely with this mycotoxin. In the present study, broiler chickens were fed diets with negligible mycotoxin levels or with naturally or artificially contaminated diets containing approximately 4000 µg/kg DON. Birds were sampled at D14 and D28. Naturally-contaminated diets caused the most harm to the birds, especially the young ones, which presented decreased jejunal villus height and increased lesions, down-regulation of a peptide transporter. At D28 broiler chickens seemed to have adapted to the dietary conditions, when no differences were observed in villus morphometry, together with up-regulation of a carbohydrate transporter. However, intestinal lesions remained present in these older birds.

Pharmacokinetics and bioavailability of tildipirosin following intravenous and subcutaneous administration in horses.

This study was designed to investigate the safety and pharmacokinetic (PK) profile of tildipirosin in horses after intravenous (i.v.) and subcutaneous (s.c.) injection of a single dose at 4 mg/kg of body weight (b.w.). A total of 12 healthy mixed breed horses were used in the study. Horses were monitored for systemic and local adverse effects, and whole blood samples were collected for hematology and plasma biochemistry analysis at time (0) and at 6, 24, and 72 h after drug administration. For PK analysis, blood samples were collected at pre-determined times before and after tildipirosin administration. Plasma concentrations of tildipirosin were determined using ultra-high-performance liquid chromatography-ultraviolet detection method (UHPLC-UV). All horses tolerated the i.v. injection of tildipirosin without showing any systemic adverse effects. However, a non-painful, soft swelling appeared at the s.c. injection site in 5 horses (41.7%). On average, tildipirosin reached a maximum plasma concentration (Cmax ) of 1257 ng/ml (geometric mean) between 0.5 and 1.5 h after s.c. administration (Tmax ). The geometric mean values for total body clearance (Cl), the apparent volume of distribution based on the terminal phase (Vz ), and the apparent volume of distribution at steady-state (Vss ) were 0.52 L/kg·h, 22 L/kg, and 10.0 L/kg, respectively. Data collected in this study suggests that tildipirosin can be used safely in horses with caution.