Journal of veterinary pharmacology and therapeutics最新文献

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 (k_a), absorption half-life (T_1/2abs), maximal plasma concentration (C_max), time to maximal plasma concentration (T_max), and area under the plasma concentration-time curve from time 0 to 96 h (AUC_{0-96 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.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are routinely used in the management of human type 2 diabetes and have been shown to effectively mitigate hyperglycemia and reduce the risks of cardiovascular and renal compromise. Two SGLT2 inhibitors, namely bexagliflozin and velagliflozin, were recently FDA approved for the treatment of uncomplicated feline diabetes mellitus. These oral hypoglycemic agents are a suitable option for many newly diagnosed cats, with rapid improvements in glycemic control and clinical signs. Suitable candidates must have some residual β-cell function, as some endogenous insulin production is required to prevent ketosis. Appropriate patient selection and monitoring are necessary, and practitioners should be aware of serious complications such as euglycemic diabetic ketoacidosis.

The purpose of this study was to evaluate the pharmacokinetics (PK) of intravenously (IV) and subcutaneously (SC) administered nalbuphine in domestic goats. Nalbuphine hydrochloride was administered at 0.8 mg/kg for both IV and SC routes in six goats with a minimum of 10-day washout period between sample collection phases. Eighteen plasma samples were collected over a 36-hour period, analyzed using reverse phase high-performance liquid chromatography (HPLC). Plasma data were analyzed using compartmental and noncompartmental approaches. Following IV nalbuphine administration, elimination half-life, area under the plasma concentration time curve from time 0 to infinity (AUC0 - ∞), concentration at time zero (C₀), and total body clearance were 120.4 ± 39.1 (min^-1 ± SD), 17311.01 ± 7227.32 (min·ng·mL^-1 ± SD), 675.6 ± 337.13 (ng·mL^-1 ± SD), and 44.5 ± 13.8 (mL·min^-1·kg^-1 ± SD), respectively. After SC nalbuphine administration, elimination half-life, area under the plasma concentration time curve from time 0 to infinity (AUC0 - ∞), and maximum plasma drug concentration were 129 ± 52.9 (min^-1 ± SD), 20826.5 ± 14376.2 (min·ng·mL^-1), and 368.03 ± 503.78 (ng·mL^-1). Calculated bioavailability for the SC route was 138 ± 126 (% ± SD). Nalbuphine in goats is characterized by rapid elimination and high subcutaneous bioavailability and may be a safe analgesic opioid option in goats in the future.

Oclacitinib is a novel Janus kinase (JAK) inhibitor that potently inhibits JAK1-dependent cytokines involved in allergy, inflammation, and pruritus (IL-2, IL-4, IL-6, IL-13, and IL-31). Oclacitinib (Apoquel®, Zoetis Inc, Parsippany, NJ) is approved for the treatment/control of pruritus associated with allergic dermatitis and treatment/control of clinical manifestations of atopic dermatitis in dogs at least 12 months of age. To evaluate the effectiveness of oclacitinib in dogs with flea allergy dermatitis, the JAK1 selective inhibitor was tested in a placebo-controlled, masked, single-dose (0.4 mg/kg) or repeat-dose (0.4 mg/kg, twice daily for 2 weeks) study. Pruritic behaviors were quantitated by video recording, and erythema and skin lesions were assessed using a 10-cm visual analog scale (VAS). Results showed that oclacitinib reduced pruritus by 61% as early as 1.5 h after a single oral dose compared to placebo, with an average reduction (compared to placebo) of 85% 1-5 h after dosing (0.4 mg/kg; p < .0001). Oclacitinib also significantly reduced erythema (p < .0001) and skin lesion (p < .0005) VAS scores on Day 14 compared to placebo in a repeat dose study. No adverse events were noted during the conduct of these studies. IL-31 concentrations were elevated in the majority of dogs after flea infestation, suggesting JAK1-dependent cytokines may drive clinical signs of flea allergy dermatitis. These findings show that oclacitinib, an inhibitor of JAK1-dependent cytokines involved in allergy and inflammation can rapidly reduce clinical signs associated with flea allergic dermatitis in dogs.

Canine urinary excretion of chloramphenicol was evaluated to optimize a dosing protocol for treating urinary tract infections. Seven healthy male intact purpose-bred Beagles and six healthy client-owned dogs of various breeds each received a single oral 50 mg/kg dose of chloramphenicol. Urine was collected at baseline, and 6, 8, 12, and 24 h after chloramphenicol. Chloramphenicol urine concentrations were measured and compared to the epidemiological cutoff value for E. coli (16 mcg/mL). At 8 h, mean chloramphenicol concentration from all dogs was 266.9 mcg/mL (90% CI 136.2-397.7 mcg/mL) but was lower in Beagles than client-owned dogs. At 12 h, mean chloramphenicol concentration from all dogs was 111.0 mcg/mL (90% CI 36.9-185.0 mcg/mL) and was lower in Beagles (10.6 mcg/mL, 90% CI 1.4-19.8 mcg/mL) than client-owned dogs (228.0 mcg/mL, 90% CI 103.0-353.1 mcg/mL). Urine half-life was similar for all dogs (1.8-3.8 h). This justifies dosing chloramphenicol 50 mg/kg PO q 8 h. All client-owned dogs additionally maintained concentrations well above 16 mcg/mL, for 12 h, suggesting that q 12-h dosing might be appropriate for non-Beagle dogs with susceptible lower urinary tract infections. A clinical trial in dogs with urinary tract infections is needed as well as further investigation into potential breed differences.

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.