Journal of veterinary pharmacology and therapeutics最新文献

Trailing endpoints are a recognised challenge in broth microdilution MIC testing, particularly for bacteriostatic agents such as trimethoprim (TMP) and sulphonamides. In this study, we applied a pharmacodynamically guided refinement to determine the MIC of the combination against Staphylococcus pseudintermedius; we did not aim at redefining clinical susceptibility, but at refining MIC determination to better guide pharmacodynamic study design. By providing more reliable thresholds for growth suppression, this approach supports optimisation of PD modelling and may ultimately inform translational applications, such as dose prediction and reducing misclassification in PD contexts. Visual MICs were compared to those derived from log₁₀ changes in CFU/mL over 24 h, using pharmacodynamic thresholds of +2.3 log₁₀ (growth from standard inoculum of 5 × 10⁵ to ~10⁸ CFU/mL, corresponding to visible growth MIC) and 0 log₁₀ change (stationary concentration). Across 10 clinical isolates, visual MICs often underestimated the concentration required to suppress growth by 2-4 fold (more than one dilution step), particularly for sulphonamides. TMP-sulphonamide combinations at a 1:19 ratio showed reduced trailing and closer agreement between visual and count-based MICs, reflecting enhanced bactericidal activity. Time-kill curve experiments anchored on the log₁₀ count-based MIC provided a well-distributed range of PD responses, capturing both suppression and killing more accurately than curves centred on visual MICs. This method supports more rational selection of concentrations for PD studies and may be especially valuable for slow-acting or ratio-sensitive combinations, and has translational value for sulphonamides, such as sulfamethoxazole, used in both human and veterinary medicine.

The aim of this study was to develop amoxicillin (AMX) dosage regimens for the treatment of Escherichia coli and Staphylococcus delphini infections in mink using a pharmacokinetic (PK) and pharmacodynamic (PD) approach. Two animal experiments with a total of 12 minks were conducted to investigate PK parameters after intravenous or oral administration of an AMX off-label dosage of 15 mg/kg. The PK characteristics of AMX were analyzed using non-linear mixed effect modeling. In vitro time kill experiments using AMX concentrations up to 16 × MIC were conducted with two E. coli and two S. delphini isolates. Semi-mechanistic modeling of time-kill experiments was subsequently done to study PD characteristics. By integrating PK and PD data, the PK/PD index and PK/PD target were predicted. Simulations were applied to determine an optimal AMX dosage. The PD model revealed higher in vitro efficacy and lower potency of AMX against E. coli compared to S. delphini. fT(%) > MIC was selected as the PK/PD index, indicating a time-dependent effect of AMX. New mink-specific AMX dosages of 50 mg/kg twice a day for E. coli infections and 7.5 mg/kg once daily for S. delphini infections were determined. The study emphasizes the need for dose optimization studies, especially for minor animal species for which antibiotics are generally used off-label.

Whitespotted bamboo sharks (Chiloscyllium plagiosum) are a common species of elasmobranchs housed in zoos and aquaria. Medical concerns like conspecific trauma and bacterial infections commonly lead to the empirical use of antibiotic medications like ceftazidime, despite limited pharmacokinetic studies in elasmobranchs. In this study, 36 whitespotted bamboo sharks were divided into six groups using a population pharmacokinetic design. They were administered a single intramuscular injection of ceftazidime at 20 mg/kg. Blood samples were collected for plasma drug concentration at time points T = 0 and 30 min, and 1, 2, 4, 6, 12, 24, 48, 72, and 96 h post-injection. Samples were analyzed by the Clinical Pharmacology Laboratory in the College of Veterinary Medicine of North Carolina State University using high-pressure liquid chromatography (HPLC) analysis. For at least 96 h, all sharks in the study maintained plasma concentrations of ceftazidime above the MIC of 4 μg/mL, which is considered susceptible when testing isolates from other animals. The long elimination half-time of 84.15 h suggests that recommended dosing intervals may be extended beyond the commonly used 3 days to at least every 96 h.

We examined the pharmacokinetics of intravenous pridinol in six thoroughbred horses. Each horse received a single 20 mg dose of pridinol mesylate via the jugular vein, and plasma and urine samples were collected over 72 h. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify pridinol concentrations in plasma and urine, allowing for the calculation of pharmacokinetic parameters. A three-compartment model best fit the plasma elimination data. Using the Toutain model, irrelevant plasma and urine concentrations were estimated to be 0.00284 and 0.000612 ng/mL, respectively. Key pharmacokinetic parameters were clearance rate, 1.27 L/h/kg; steady-state volume of distribution, 2.07 L/kg; and steady-state urine-to-plasma ratio, 0.211. These findings can help establish regulatory thresholds for pridinol in horse racing and equestrian sports.

Remimazolam (RMZ) is a new short-half-life benzodiazepine used in humans. We compared the pharmacokinetics and sedative effects of RMZ with those of midazolam (MDZ) in Thoroughbred horses. Six Thoroughbreds received a single IV dose of RMZ 0.05 mg/kg or MDZ 0.05 mg/kg in a randomized crossover design. Blood samples were collected, and plasma RMZ and MDZ concentrations were measured by LC-MS/MS. Plasma concentrations were analyzed by using non-compartmental analysis and a nonlinear mixed effect model. The half-life of RMZ (0.77 ± 0.15 h) was significantly shorter than that of MDZ (3.7 ± 0.3 h). The bootstrap estimates of the parameters (mean ± SD) for RMZ and MDZ were 14.0 ± 1.1 L/kg/h and 0.45 ± 0.02 L/kg/h for clearance; 2.01 ± 0.26 L/kg and 1.31 ± 0.10 L/kg for the distribution volume of steady state. RMZ clearance was significantly higher than MDZ clearance in a comparison of post hoc values for the six horses. Wobble, observed as muscle relaxation/ataxia and a diminished stimulus response to RMZ, was observed from immediately after administration until 5 min later; the response generally disappeared after 10 min. Clinical trials will determine the place of RMZ in total intravenous anesthesia for rapid and smooth recovery in horses.

The fluoroquinolone antimicrobial agents, enrofloxacin and marbofloxacin, were approved in the United States for cats in 1990 and 2001, respectively. In 2023, revised breakpoints for testing isolates from dogs were published. These canine breakpoints are discordant with the current feline breakpoints. This study was aimed at suggesting new feline breakpoints using a pharmacokinetic-pharmacodynamic (PK-PD) approach and new pharmacokinetic data. The PK-PD derived cutoff values (CO_PD) were compared to microbiologic data available for testing the susceptibility of targeted pathogens since the original approval. Compared to the current Clinical and Laboratory Standards Institute (CLSI) breakpoints for enrofloxacin and marbofloxacin in cats, these revised breakpoints are lower by two dilutions for the Enterobacterales, Pseudomonas aeruginosa, Staphylococcus spp., and Pasteurella multocida. Isolates that may have previously tested susceptible (S) may test resistant (R) using these suggested breakpoints. We also are suggesting a susceptible dose-dependent (SDD) category for testing marbofloxacin against these isolates from cats that allows for a higher dose. These suggested breakpoints may be considered by laboratories, standard-setting organizations, and industry sponsors of these antimicrobials for testing common bacteria isolated from cats.

There has been a growing interest in the use of cannabinoids in horses in recent years. Several studies have reported on the pharmacokinetics of cannabidiol (CBD) in horses. However, cannabidiolic acid (CBDA) has received less attention, despite limited evidence suggesting clinically beneficial effects in other species. Horses were administered 3 mg/kg of CBD, 3 mg/kg of CBDA, and a placebo per os in a crossover design, with a one-week washout period between treatments. Plasma and urine samples were collected and analyzed using ultra high-performance liquid chromatography coupled to tandem mass spectrometric. Observed CBDA plasma concentrations were up to 67 times higher, and the CBDA area under the plasma concentration-time curve was up to 36 times larger than those of CBD. Median terminal half-lives in plasma were 7.8 h for CBD and 5.3 h for CBDA. Both compounds were detectable in plasma for up to 72 h. In urine, CBD and CBDA were detectable for 168 and 72 h, respectively. The results suggest greater intestinal uptake or lower first-pass metabolism/clearance of CBDA compared to CBD. Given the poor oral bioavailability of CBD in horses, CBDA may hold greater clinical relevance. Further studies are needed to elucidate the pharmacokinetics and pharmacodynamics of CBDA in horses.

Oxolinic acid (OA) is a widely recommended antimicrobial agent for managing Gram-negative bacterial infections in aquaculture. This study investigates the pharmacokinetics and withdrawal period of OA in Trachinotus blochii, a high-value mariculture species, under tropical conditions. A single oral dose of 12 mg/kg was administered, and OA levels were quantified using Liquid Chromatography-Tandem Mass Spectrometry across 12 time points from plasma, intestine, liver, kidney, and gills. Maximum concentrations (C_max) were reached within 6 h (T_max). C_max (μg/Kg) followed the order: plasma (99.77) < liver (666.67) < intestine (1764.67) = gill (1776.67) = kidney (1783.33). The elimination half-life (T_½) was longest in the kidney, followed by the liver and intestine, whereas plasma and gills exhibited faster elimination. Tissue/plasma ratios were 4.6 (liver), 8.4 (gill), 13.95 (kidney), and 17.12 (intestine). The results demonstrated that OA was rapidly absorbed from the intestine, distributed extensively, and eliminated quickly through renal, intestinal, and branchial routes. The kidney played a key role in OA elimination. In the withdrawal study, after 7 days of in-feed administration at the therapeutic dose, OA exceeded the recommended maximum residue limit in edible tissues at 6 h. The drug levels dropped below detectable limits within 24 h. Applying a 30% safety margin, a withdrawal period of 31.2 h (or 37.7°C- days) is recommended. The findings provide a practical framework for the responsible and effective use of OA in T. blochii mariculture, promoting aquaculture sustainability and food safety.

The purpose of this study was to evaluate the pharmacokinetics of oral (PO) ondansetron compared to intravenous (IV) ondansetron in eight healthy client-owned dogs. Dogs were randomized to one of two protocols in a crossover design, receiving PO or IV ondansetron at a dose of 1 mg/kg on Day 0 and the opposite formulation at an equal dose on Day 7. Plasma was collected at baseline and 1, 2, 4, and 8 h post administration. Ondansetron concentrations were measured utilizing liquid chromatography/mass spectrometry. For IV administration, AUC_0-8h was 1181 ± 619 ng/mL*h, with all dogs having detectable plasma concentrations at all time points. For PO administration, mean C_max was 22 ± 11.3 ng/mL and AUC_0-8h was 61.7 ± 45.4 ng/mL*h, with all dogs having undetectable concentrations at various time points. Oral mean bioavailability was estimated at 5.2% ± 2.1%. Oral bioavailability of ondansetron is very low in healthy dogs, raising concern for the efficacy of ondansetron when given orally at 1 mg/kg. Future studies evaluating pharmacodynamics of ondansetron in nauseous client-owned dogs should be performed to investigate whether plasma drug concentrations are the optimal way to assess the efficacy of oral ondansetron.

Ilunocitinib, a novel Janus kinase inhibitor, is indicated for managing pruritus and skin lesions associated with canine allergic and atopic dermatitis. Pharmacokinetics of ilunocitinib were investigated following single intravenous and oral administrations, both in fed and fasted states. Dose proportionality was assessed using oral doses ranging from 0.4 to 4.0 mg/kg, and multiple dosing was evaluated with daily oral doses of 0.8 mg/kg. Serial blood samples were collected, and plasma concentrations of ilunocitinib were measured using a validated LC-MS/MS method. Pharmacokinetic samples were also collected in field trials. Intravenous administration resulted in low plasma clearance (0.437 L/h/kg), a volume of distribution of 1.58 L/kg, and a terminal half-life of 4.4 h. Oral administration led to rapid absorption (T_max usually ranging between 1 and 4 h) and higher bioavailability in fed dogs (80%) compared to fasted dogs (61%). The prandial effect observed in laboratory studies with single doses was not clinically relevant under field conditions. Exposure increased less than proportionally with increasing doses. No clinically relevant accumulation was observed with 0.8 mg/kg daily dosing. No sex-based differences were observed. Altogether, ilunocitinib pharmacokinetics support a once-daily oral dosing in dogs. Minimal accumulation, also confirmed in long-term studies, further supports the safety of ilunocitinib with a daily dosing regimen.