Journal of veterinary pharmacology and therapeutics最新文献

Iron deficiency anemia (IDA) and cystoisosporosis are the most common clinical conditions of fast-growing piglets. Until now, IDA and cystoisosporosis have been managed by intramuscular injection of iron complexes (such as dextran or gleptoferron) and oral administration of toltrazuril. Recently, a new combination product containing toltrazuril and gleptoferron for intramuscular application (Forceris®) has been registered. The objective of this study was to compare the pharmacokinetic profiles of toltrazuril and its main metabolite, toltrazuril sulfone, following a single oral (Baycox®) or intramuscular (Forceris®, a toltrazuril-iron combination product) administration at 20 mg/kg to young suckling piglets. The orally treated piglets were also supplemented with iron (Gleptosil®), and the hematinic activities were compared. Piglets in both groups received comparable doses. The peak concentration (C_max) of toltrazuril after intramuscular administration was 11% lower than that after oral administration (p = .376). However, the exposure to toltrazuril (AUC) was significantly increased (40% higher) when toltrazuril was administered intramuscularly (p = .036). The C_max and AUC values of the active metabolite, toltrazuril sulfone were 39% and 34% higher, respectively, after intramuscular administration (p = .007 and 0.008, respectively). Piglets in both groups were properly protected against IDA. In conclusion, a higher relative bioavailability of toltrazuril is observed when toltrazuril is administered intramuscularly.

Clodronic acid is designated as a controlled medication for competition horses by the International Federation for Equestrian Sports and, according to the International Federation of Horseracing Authorities, clodronic acid is not to be administered to racehorses younger than 3.5 years or within 30 days prior to a race. In this study, 35 horses involved in competition were treated with a single dose of 1.53 mg clodronic acid/kg bodyweight intramuscularly. Plasma samples were obtained before treatment and 10, 20, 30, and 40 days post-administration. Clodronic acid concentrations were measured using a validated method, and the data were fitted using a nonlinear mixed effects model. The estimated depletion half-life of clodronic acid was 10.6 days (inter-individual variability: 17.9%). Age, body weight, sex, disease severity, dose, training days, training, and competition did not significantly impact the depletion half-life. The percentage of horses predicted via simulation to have clodronic acid concentrations below the assay's limit of quantification of 1.0 ng/mL was 93.9% at day 30 and 99.4% at Day 40. This study provides rationale to the equestrian federations and horse racing authorities to reliably establish a detection time for clodronic acid, assisting equine veterinarians in recommending a competition withdrawal time for the horses under their care.

Orthologs of breast cancer resistance protein (BCRP/ABCG2), an ATP-binding cassette (ABC) efflux transmembrane transporter, are present in several species. The list of compounds known to interact with BCRP is growing, and many questions remain concerning species-specific variations in substrate specificity and affinity and the potency of inhibitors. As the most abundant efflux transporter known to be present in the blood–milk barrier, BCRP can increase the elimination of certain xenobiotics to milk, posing a risk for suckling offspring and dairy product consumers. Here we developed a model that can be employed to investigate species-specific differences between BCRP substrates and inhibitors. Membrane vesicles were isolated from transiently transduced human embryonic kidney (HEK) 293 cells, overexpressing BCRP, with human, bovine, caprine, and ovine cDNA sequences. To confirm BCRP transport activity in the transduced cells, D-luciferin efflux was measured and to confirm transport activity in the membrane vesicles, [³H] estrone-3-sulfate ([³H]E₁S) influx was measured. We also determined the Michaelis–Menten constant (Km) and Vmax of [³H]E₁S for each species. We have developed an in vitro transport model to study differences in compound interactions with BCRP orthologs from milk-producing animal species and humans. BCRP transport activity was demonstrated in the species-specific transduced cells by a reduced accumulation of D-luciferin compared with the control cells, indicating BCRP-mediated efflux of D-luciferin. Functionality of the membrane vesicle model was demonstrated by confirming ATP-dependent transport and by quantifying the kinetic parameters, Km and Vmax for the model substrate [³H]E₁S. The values were not significantly different between species for the model substrates tested. This model can be insightful for appropriate inter-species extrapolations and risk assessments of xenobiotics in lactating woman and dairy animals.

Tilmicosin (TMC), a semi-synthetic macrolide antibiotic, is widely used in veterinary medicine due to its broad-spectrum, bacteriostatic properties. Frequently administered in various birds species, it is likely used off-label in geese as well. The study sought to investigate TMC's pharmacokinetics, tissue residues, in geese through in vivo experiments. The study involved longitudinal open studies on 15 healthy adult males, with three phases separated by one-month washout periods. Geese were administered TMC through intravenous (IV, 5 mg/kg), subcutaneous (SC, 10 mg/kg), and oral (PO, 25 mg/kg for five consecutive days) routes, with blood samples drawn at specific intervals. Tissue samples were also collected for subsequent analysis at pre-assigned times. TMC in goose plasma was quantified by a fully validated HPLC method. Plasma concentrations were quantified up to 4 hr for the PO and IV routes, and up to 10 hr in the SC route. Significant variations in bioavailability were observed between SC (87%) and PO (4%) routes. The body extraction ratio was low at 0.03, suggesting minimal ability of the liver and kidneys to eliminate TMC. Multiple oral doses showed no plasma accumulation, but tissue data revealed extensive distribution and prolonged residence, up to 120 h, suggesting a sustained therapeutic effect despite the brief plasma half-life. Regarding the multiple PO doses, provisional withdrawal times of 6, 7.5, and 8 days were suggested for the liver, muscles, and kidneys, respectively, according to the MRL set for these matrices in chickens by EMA. In conclusion, while the practical oral administration is discouraged at the population level, SC administration of TMC may be appropriate for geese, albeit impractical for flock therapy.

N-acetyl-l-cysteine (NAC) has been suggested as an antioxidant that can alleviate the negative effects of stress conditions in broilers. However, knowledge of its pharmacokinetics (PK) in this avian species is very limited. Therefore, the study aimed to shed more light on the PK properties of NAC in chickens. Broilers were subjected to single intravenous (i.v.) or oral (p.o.) treatment or multiple NAC administrations via the feed. Drug concentrations were determined by LC–MS/MS, and the data were subjected to non-compartmental analysis and modeled by non-linear mixed effect approach. NAC was eliminated in a short time after i.v. treatment, with a t _1/2el of 0.93 (0.59–2.09) h. It showed limited distribution with population mean of volumes of distribution in the central and peripheral compartments V ₁ of 0.148 L/kg and V ₂ of 0.199 L/kg, respectively, and V _darea of 0.39 (0.258–0.635) L/kg. The value of MRT was 1.76 h (range of 0.96–2.69, p < .05) after single p.o. treatment, indicating a twofold increase if compared to i.v. administration (0.87 h, 0.55–1.78). Both methods of Pk analysis revealed very limited bioavailability, <10%. Feeding behavior led to a later achievement of lower maximum plasma concentrations (5.74, range of 3.44–9.32 μg/mL, p < .05), which were maintained during the 5 days of treatment.

There is currently limited pharmacokinetic data for the use of famotidine in goats for treatment and prevention of abomasal ulceration. The objective of this study was to determine the pharmacokinetic parameters after a single intravenous administration of famotidine (0.6 mg/kg). Famotidine was administered to six healthy goats and plasma samples were collected over a 24-h period. The famotidine concentration was measured using reverse phase high-performance liquid chromatography (HPLC). Non-compartmental analysis was then used to determine the pharmacokinetic parameters. The maximum plasma concentration was estimated at 5476.68 ± 1530.51 ng/mL and elimination half-life was estimated at 18.455 ± 13.26 min. The mean residence time was determined to be 19.85 ± 12.14 min with the apparent volume of distribution being estimated at 321.924 ± 221.667. The area under the curve was determined to be 54230.08 ± 24947.6 min*ng/mL. Total exposure and elimination half-life were less than what has been reported in cattle and horses. Future research evaluating the pharmacokinetics of subcutaneous administration and looking at the pharmacodynamics of famotidine in goats is needed to determine the effectiveness of famotidine on raising pH levels of the abomasum.

Clonazepam causes sedation and psychomotor impairment in people. Due to similarities between people and swine in response to benzodiazepines, clonazepam may represent a viable option to produce mild-to-moderate tranquillization in pigs. The objective of this study was to determine the pharmacokinetic profile of a single oral dose (0.5 mg/kg) of clonazepam in eight healthy, growing commercial cross pigs. Serial plasma samples were collected at baseline and up to 96 h after administration. Plasma concentrations were quantified using reverse-phase high-performance liquid chromatography, and compartment models were fit to time–concentration data. A one-compartment first-order model best fits the data. Maximum plasma concentration was 99.5 ng/mL, and time to maximum concentration was 3.4 h. Elimination half-life was 7.3 h, mean residence time 7.4 h, and apparent volume of distribution 5.7 L/kg. Achieved plasma concentrations exceeded those associated with psychomotor impairment in people although pharmacodynamic effects have not been investigated in pigs. A simulated oral regimen consisting of 0.35 mg/kg administered every 8 h to pigs would achieve plasma concentrations above 32 ng/mL which are shown to produce psychomotor impairment in people. Further studies to test the clinical efficacy of these dosages in commercial and miniature pigs are warranted.

Butorphanol is commonly administered, both by the intravenous and intramuscular routes, to racehorses to facilitate handling for diagnostic procedures. As the administration of butorphanol for therapeutic purposes is considered appropriate, in order to avoid inadvertent positive drug tests, a thorough understanding of the pharmacokinetics of this drug is necessary. In the current study, 12, exercised Thoroughbred horses were administered a single intramuscular dose of 0.1 mg/kg butorphanol, and serum and urine samples were collected at various times post drug administration for determination of butorphanol concentrations using a highly sensitive liquid chromatography tandem mass spectrometry method. Serum data were modeled using a nonlinear mixed effect population PK model. The maximum concentration (C _max) and time to maximum concentration (T _max) were 139.9 ± 72.8 ng/mL and 0.43 ± 0.44 h (mean ± SD), respectively. Although likely not clinically relevant, but important for drug testing purposes, a prolonged terminal phase was observed, yielding a terminal half-life of 7.67 ± 1.86 h. Using the blood screening limits proposed by the Horseracing Integrity and Welfare Unit, the detection time for intramuscular administration of butorphanol was estimated to be 96 h.

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 (AUC_0–48) 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 recent years, especially since the COVID-19 pandemic, the number of predatory journals has increased significantly. Predatory journals exploit the “open-access model” by engaging in deceptive practices such as charging high publication fees without providing the expected quality and performing insufficient or no peer review. Such behaviors undermine the integrity of scientific research and can result in researchers having trouble identifying reputable publication opportunities, particularly early-career researchers who struggle to understand and establish the correct criteria for publication in reputable journals. Publishing in journals that do not fully cover the criteria for scientific publication is also an ethical issue. This review aimed to describe the characteristics of predatory journals, differentiate between reliable and predatory journals, investigate the reasons that lead researchers to publish in predatory journals, evaluate the negative impact of predatory publications on the scientific community, and explore future perspectives. The authors also provide some considerations for researchers (particularly early-career researchers) when selecting journals for publication, explaining the role of metrics, databases, and artificial intelligence in manuscript preparation, with a specific focus on and relevance to publication in veterinary medicine.