Journal of veterinary pharmacology and therapeutics最新文献

Letrozole is a non-steroidal, third-generation aromatase inhibitor used in humans. Although letrozole is not approved for use in animals, it is used off-label in cases of synchronization and infertility. The aim of this study was to determine the pharmacokinetics of letrozole after a single intravenous administration at three different doses in ewes during the breeding season and its effect on gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) at the beginning of proestrus. The study was carried out on 24 healthy Merino ewes. Ewes were randomly divided into four groups (n = 6) as control, 0.5, 1, and 2 mg/kg. Plasma concentrations of letrozole were measured using HPLC-UV and were analyzed by non-compartmental analysis. LH and FSH concentrations were measured with a commercial ELISA kit. The terminal elimination half–life (t_1/2ʎz) was significantly prolonged from 11.82 to 18.44 h in parallel with the dose increase. The dose-normalized area under the concentration–time curve (AUC) increased, and total body clearance (Cl_T) decreased at the 1 and 2 mg/kg doses (0.05 L/h/kg) compared with the 0.5 mg/kg dose (0.08 L/h/kg). There were no differences in the volume of distribution at steady-state and initial (C_0.083h) plasma concentration values between dose groups. The decreased Cl_T, prolonged t_1/2ʎz, and increased AUC at increasing doses showed the nonlinear kinetic behavior of letrozole. Letrozole significantly reduced LH concentration without affecting FSH concentration at all doses. As a result, letrozole has the potential to be used in synchronization methods and manipulation of the follicular waves due to its effect on LH secretion.

Meloxicam is routinely used for pain alleviation in pre-ruminant calves during husbandry procedures. The pharmacokinetics of a single dose (0.5 mg/kg) of meloxicam was investigated after intravenous (IV), subcutaneous (SC), and oral (PO) administration in 30 pre-ruminant calves. Each group included 10 calves. Oral meloxicam was administered at least 1 h after feeding. Plasma samples were collected for up to 168 h, and the meloxicam concentration was analysed with liquid chromatography and mass spectrometry, followed by a noncompartmental pharmacokinetic analysis. The maximum meloxicam concentrations in plasma were 1.91 ± 0.27 μg/mL and 1.77 ± 0.16 μg/mL after SC and PO routes, respectively. The time of maximum concentration was 7.6 ± 2.8 h after SC and 10.0 ± 5.7 h after PO administration. The approximate bioavailability of meloxicam was 97% for SC and PO routes. The elimination half-lives were 79.2 ± 12.4, 84.6 ± 24.8, and 84.8 ± 22.3 h after IV, SC, and PO routes, respectively. The results suggest that the therapeutic meloxicam concentrations in plasma that are required for pain relief in other species, such as horses, may be maintained for several days following a single dose (0.5 mg/kg) administered IV, SC, or PO in calves.

Enrofloxacin (ENR) is widely used in aquaculture practice, but little is known about its pharmacokinetic, withdrawal period and dietary risk in fish via bath administration. The purpose of this study was to provide data support for the use of ENR bath therapy in the northern snakehead (Channa argus). The pilot study was carried out to evaluate the therapy concentrations of ENR in northern snakehead with immersion concentrations ranged from 5 to 40 mg/L for 6 h. Based on results of the pilot study, an ENR immersion concentration of 20 mg/L was used for the formal experiment. At this dose, the peak concentrations of ENR in plasma, muscle plus skin, liver and kidney were 4.85, 4.55, 3.87 and 7.42 μg/mL (or g), respectively. According to the AUC_0-∞ values, the distribution of ENR in northern snakehead followed the order of kidney > plasma > liver > muscle + skin. The elimination of ENR in northern snakehead was very slow, the half-lives (T_1/2λz) were up to 90.31, 85.5, 104.56 and 120.9 h in plasma, muscle plus skin, liver and kidney, respectively. Ciprofloxacin (CIP) was not detected in any samples in the pilot study and was only occasionally detected in muscle plus skin and liver samples in formal experiment. Based on the calculated PK/PD index AUC/MIC and C_max/MIC, the current bath treatment regimen will have a good therapeutic effect on infections caused by bacteria with MIC below 0.6 μg/mL. The dietary risk assessment suggested that there was a dietary risk (Hazard Quotients > 10%) until day 6 after bath treatment. It is mandatory for ENR to maintain a withdrawal period of at least 450°C-day in northern snakehead after bath treatment ceased.

The benzenedisulfonamide derivative clorsulon is a potent fasciolicide which is marketed in fixed combination injectables, typically combined with the macrocyclic lactone ivermectin. In the presented pharmacokinetic study, the plasma profile of clorsulon in 32 healthy, young Brown Swiss cattle was administered a single intravenous dose at 3 mg/kg body weight or subcutaneously at 3, 6 or 12 mg/kg body weight (4 intact male and 4 female animals per treatment) as a 30% w/v clorsulon injection formulation. Serial blood samples were collected up to 24 days after administration to establish the pharmacokinetics, bioavailability and dose proportionality of clorsulon. Following a single intravenous injection of clorsulon at 3 mg/kg body weight, the area under the concentration versus time curve from the start of dose administration to the time of the last quantifiable concentration (AUC_last) was 4830 ± 941 day*ng/mL, and half-live was 2.37 ± 0.98 days. The back extrapolated concentration at time 0 was 38,500 ± 6070 ng/mL. The volume of distribution at steady state and clearance were 685 ± 107 mL/kg and 664 ± 127 mL/day/kg, respectively. In the groups dosed at 3, 6 or 12 mg/kg body weight by subcutaneous injection, clorsulon plasma concentrations rose to maximum within 0.5 day and decreased to the last sample point. For these groups, the maximum plasma clorsulon concentrations were 3100 ± 838, 5250 ± 1220 and 10,800 ± 1730 ng/mL, respectively, and the AUC_last was 5330 ± 925, 9630 ± 1300 and 21,500 ± 3320 day*ng/mL, respectively. Half-lives, 2.01 ± 0.62, 3.84 ± 1.42 and 5.36 ± 0.60 days, respectively, increased significantly with dose, likely related to increasing dose volume. Clorsulon was well absorbed and fully bioavailable (103%–114%) after subcutaneous injection. No gender-related difference in systemic exposure was observed. Assessment of C_max and AUC_last demonstrated a proportional increase in systemic exposure to the clorsulon subcutaneous doses over the range of 3–12 mg/kg body weight.

This study evaluated four different formulations of itraconazole and amiodarone. Formulation 1 was Vida's combination tablet containing both active pharmaceutical ingredients (APIs). Formulation 2 was separate, commercially available human generic capsules and tablets of itraconazole and amiodarone, respectively. Formulation 3 was separate, compounded suspensions of itraconazole and amiodarone. Formulation 4 was a compounded chewable tablet of itraconazole. Eight female dogs were dosed with 5 mg/kg of itraconazole and 15 mg/kg amiodarone (except for formulation 4, which only received 5 mg/kg itraconazole) once weekly for 4 weeks using a modified Latin Square design, ensuring that all dogs received all formulations with a 7-day washout between treatments. Animals were fasted overnight prior to each dose administration, with food returned to all animals 4 h post-dose. Blood samples (3 mL) were collected pre-treatment (0) and at appropriate time points over 72 h after each dose for a total of 14 samples per dog per treatment. There was high variability in the serum concentration data within treatment groups for itraconazole. The compounded suspensions were difficult to dose due to the nature of the formulations. The volumes dosed were accurate and consistent, but the suspension was thin and settled immediately when shaking was stopped for both itraconazole and amiodarone. All serum samples following itraconazole chewable tablet administration were not detectable or just above itraconazole's LOQ and thus did not allow for pharmacokinetic determination.

This study aimed to evaluate the pharmacokinetics (PK) of tranexamic acid (TXA) in horses and estimate its irrelevant plasma and urine concentrations using the pharmacokinetic/pharmacodynamic (PK/PD) approach by applying the Pierre-Louis Toutain model. TXA was intravenously administered to eight thoroughbred mares, and plasma and urine TXA concentrations were quantified by liquid chromatography/tandem mass spectrometry. The quantified data were used to calculate the PK parameters of TXA in horses. The plasma elimination curves were best-fitted to a three-compartment model. Using the Toutain model approach, irrelevant plasma and urine TXA concentrations were estimated to be 0.0206 and 0.997 μg/mL, respectively. The typical values of clearance, steady-state volume of distribution, and steady-state urine-to-plasma ratio were 0.080 L/kg/h, 0.86 L/kg, and 49.0, respectively. The obtained irrelevant concentrations will be useful for establishing relevant regulatory screening limits for effective control of TXA use in horse racing and equestrian sports.

Dexamethasone is approved for cattle in Canada for several conditions, but no withdrawal times are currently provided on the approved labels. Recently, the list of Maximum Residues Limits for Veterinary Drugs in Foods in Canada was amended to include dexamethasone. The objectives of this study were to determine the residue depletion profile of dexamethasone after an extra-label dosage regimen in milk of healthy lactating dairy cattle (n = 18) and in edible tissues of healthy beef cattle (n = 16) and to suggest withdrawal intervals. Dexamethasone was administered intramuscularly at 0.05 mg/kg daily for 3 days. Milk samples were collected prior to treatment and every 12 h up to 96 h post-dose. Muscle, liver, kidney, and peri-renal fat tissues were collected from beef cattle at 3, 7, 11, or 15 days post-dose. Dexamethasone analysis was performed by liquid chromatography/mass spectrophotometry. Dexamethasone residues were detected in milk samples up to 36 h. Muscle and fat had no detectable dexamethasone residues while kidney and liver had detectable residues only on day 3 post-dose. A withdrawal interval of 48 h for milk in Canadian dairy cattle and 7 days for meat in Canadian beef cattle are suggested for the dexamethasone treatment regimen most commonly requested to CgFARAD™.

In aquaculture, oxolinic acid (OA) is used as a second-line treatment at 12 mg/kg biomass/day for seven consecutive days. The present study evaluated the biosafety of 21 days of dietary administration of OA at 0, 12, 36, 60 and 120 mg by assessing the growth, biochemical, erythrocytic morphological and histopathological alterations and residue levels in Oreochromis niloticus. A significant dose-dependent reduction in feed intake and biomass and an increase in mortalities and erythrocytic cellular and nuclear changes were recorded. Significant elevations in plasma glucose, creatinine, alkaline phosphatase, alanine transaminase and aspartate transaminase and a decline in calcium and chloride levels were documented. The kidney, liver and intestine histoarchitecture showed mild to marked alterations. The edible tissue OA residues peaked on day 21 and decreased upon cessation of administration in all the dosing groups. The residue levels in the muscle of the recommended dose group were well within the maximum residue limit set by the European Medicines Evaluation Agency. Although the current study hinted at the safety and tolerability of OA even during long-term usage in O. niloticus in Indian conditions, care must be exercised for its aquacultural application because of its listing as a critically important medicine for humans.

The pharmacokinetics were described of meloxicam (MLX) in green sea turtles (Chelonia mydas), following a single intravenous (i.v.) and intramuscular (i.m.) administrations at one of two dosages of 0.1 or 0.2 mg/kg body weight (b.w.). The sample of 20 green sea turtles was divided into four groups (n = 5) using a randomization procedure according to a parallel study design. Blood samples were collected at pre-assigned times up to 168 h. MLX in the plasma was cleaned-up and quantified using a validated high-performance liquid chromatography method with UV detection. The concentration of MLX in the experimental green sea turtles with respect to time was pharmacokinetically analyzed using a non-compartment model. MLX plasma concentrations were quantifiable for up to 72 and 120 h after i.v. at dosages of 0.1 and 0.2 mg/kg b.w., respectively, whereas it was measurable for up to 168 h after i.m. administration at both dosages. The long elimination half-life value of MLX (28 h) obtained in green sea turtles after i.v. administration was consistent with the quite slow clearance rate for both dosages. The average maximum concentration (C_max) values of MLX were 1.05 μg/mL and 4.26 μg/mL at dosages of 0.1 and 0.2 mg/kg b.w., respectively, with their elimination half-life values being 37.26 h and 30.64 h, respectively, after i.m. administrations. The absolute i.m. bioavailability was approximately 110%. These results suggested that i.m. administration of MLX at a dosage of 0.2 mg/kg b.w. was likely to be effective for clinical use in green sea turtles (Chelonia mydas). However, further studies are needed to determine the pharmacodynamic properties and clinical efficacy of MLX for the treatment of inflammatory disease after single and multiple dosages.

Toltrazuril (TZR) is currently the only registered chemotherapeutic drug in the European Union for the treatment of Cystoisospora suis. This study investigated the comparative pharmacokinetics and tissue concentration-time profiles of TZR and its active metabolite, toltrazuril sulfone (TZR-SO₂), after oral (per os, p.o.) and intramuscular (i.m.) administration to suckling piglets. Following a single administration of TZR orally at 50 mg/piglet or intramuscularly at 45 mg/piglet, higher concentrations of TZR and TZR-SO₂ were observed in all three investigated tissues after p.o. administration. The mean TZR concentration in serum peaked at 14 μg/mL (34.03 h) and 5.36 μg/mL (120 h), while TZR-SO₂ peaked at 14.12 μg/mL (246 h) and 9.92 μg/mL (330 h) after p.o. and i.m. administration, respectively. TZR was undetectable in the liver after p.o. administration (18 days) and in the jejunum (24 days) after i.m. injection, while TZR-SO₂ was still detectable in all three tissues after 36 days regardless of administration routes. This study showed that p.o. formulation exhibited faster absorption and higher serum/tissue TZR/TZR-SO₂ concentrations than i.m. formulation. Both formulations generated sufficient therapeutic concentrations in the serum and jejunum, and sustained enough time to protect against Cystoisospora suis infection in the piglets.