Age-related changes in the pharmacokinetics of meloxicam after intravenous administration in sheep.

The pharmacokinetics of meloxicam was studied in 1-, 6-, and 12-month-old sheep following a single intravenous (i.v.) dose of 1 mg/kg. The experiments were carried out when the Romanov sheep were 1 month old (7.93 ± 0.91 kg), 6 months old (27.47 ± 4.91 kg), and 12 months old (37.10 ± 3.64 kg). Meloxicam concentration in plasma was determined by high-performance liquid chromatography and the data collected were evaluated by non-compartmental kinetic analysis. Meloxicam was detected in the plasma up to 72 h following i.v. administration in all age groups. The volume of distribution at steady state (Vdss ) and total body clearance (ClT ) were significantly higher in 1-month-old (304.87 mL/kg and 16.57 mL/h/kg) than in 12-month-old (193.43 mL/kg and 10.50 mL/h/kg) sheep. The area under the concentration-time curve from 0 to 72 h value of meloxicam was lower in 1-month-old (58.51 h*µg/mL) compared to 12-month-old (92.59 h*µg/mL) sheep. There was no difference in t1/2ʎz value in different age groups. The body extraction ratio values for meloxicam ranged from 0.0186 to 0.0719 after i.v. administration in all age groups. Meloxicam showed an increase in plasma concentration and a decrease in Vdss and ClT in 12-month-old compared to 1-month-old sheep. Compared to 1-month-old and 12-month-old sheep, there was no difference in these parameters in 6-month-old sheep. Because the age of sheep has an influence on the pharmacokinetics of meloxicam, dosage apparently may need to be adjusted for age.

Pharmacokinetics of cefquinome in rainbow trout (Oncorhynchus mykiss) after intravascular, intraperitoneal, and oral administrations.

This study aimed to determine the pharmacokinetics and bioavailability of cefquinome in rainbow trout (Oncorhynchus mykiss) following intravascular (IV), intraperitoneal (IP), and oral (PO) administrations at 14 ± 1°C. In this study, three hundred and six clinically healthy rainbow trout (110-140 g) were used. The fish received single IV, IP, and PO injections of cefquinome at 10 mg/kg dose. The plasma concentrations of cefquinome were measured using HPLC-UV and were evaluated using non-compartmental analysis. Cefquinome was measured up to 96 h for PO route and 144 h for IV and IP routes in plasma. Following IV administration, t1/2ʎz , ClT , and Vdss were 18.85 h, 0.037 L/h/kg, and 0.84 L/kg, respectively. The Cmax of IP and PO routes was 9.75 and 1.64 µg/ml, respectively. The bioavailability following IP and PO administrations was 59.46% and 12.33%, respectively. Cefquinome at 10 mg/kg dose may maintain T > MIC above 40% at 72 and 96 h intervals, respectively, following the IP and IV routes for bacteria with MIC values of ≤2 µg/ml and at 24 h intervals following the PO route for bacteria with MIC value of ≤0.75 µg/ml. However, further studies are needed to determine in vitro and in vivo antibacterial efficacy and multiple dosage regimens of cefquinome against pathogens isolated from rainbow trout.

Pharmacokinetics of furosemide in goats following intravenous, intramuscular, and subcutaneous administrations.

Furosemide, a loop diuretic drug, is recommended for use in cases of edema, ascites, congestive heart failure, toxicosis, and acute renal failure in goats. However, its pharmacokinetics and bioavailability have not been reported yet in this species. The aim of this study was to determine the pharmacokinetics and bioavailability of furosemide in goats following intravenous (IV), intramuscular (IM), and subcutaneous (SC) administrations at a dose of 2.5 mg/kg. Six clinically healthy goats received furosemide by each route in a three-way crossover pharmacokinetic design with a 15-day washout period between administrations. The plasma concentrations of furosemide were determined using the high-performance liquid chromatography-UV method and analyzed by non-compartmental analysis. The elimination half-life following IV, IM, and SC administration was 0.71 (0.67-0.76) h, 0.69 (0.61-0.74) h, and 0.70 (0.67-0.79) h, respectively. The volume of distribution at steady state and total clearance for the IV route were 0.17 (0.16-0.19) L/kg and 0.30 (0.27-0.33) L/h/kg, respectively. The peak plasma concentrations of furosemide following IM and SC administrations were 11.19 (10.33-11.95) and 6.49 (5.92-7.00) µg/ml at 0.23 (0.16-0.25) and 0.39 (0.33-0.42) h, respectively. The bioavailability was 109.84 (104.92-116.99)% and 70.80 (55.77-86.67)% for the IM and SC routes, respectively. The pharmacokinetics of furosemide following the IV, IM, and SC administrations in goats demonstrated significant differences, which may have clinical and toxicological implications requiring further investigations.

Effect of ketoprofen and tolfenamic acid on intravenous pharmacokinetics of ceftriaxone in sheep.

In this study, the pharmacokinetics of ceftriaxone (40 mg/kg) was determined following a single intravenous (IV) administration of ceftriaxone alone and co-administration with ketoprofen (3 mg/kg) or tolfenamic acid (2 mg/kg) in sheep. Eight healthy Akkaraman sheep (2.4 ± 0.3 years and 44 ± 4 kg of body weight) were used. The study was carried out according to the longitudinal design in three periods with a 15-day washout period between administrations. In the first period, sheep received ceftriaxone alone via an IV injection. In the second and third periods, the same sheep received ceftriaxone in combination with ketoprofen and tolfenamic acid, respectively. Plasma concentrations of ceftriaxone were assayed by high-performance liquid chromatography and analyzed using non-compartmental analysis. Following the administration of ceftriaxone alone, the elimination half-life (t1/2ʎz ), area under the plasma concentration-time curve from zero (0) hours to infinity (∞) (AUC0-∞ ), total clearance (ClT ), and volume of distribution at steady state were 1.42 h, 182.41 h*µg/ml, 0.22 L/h/kg, and 0.17 L/kg, respectively. While ketoprofen and tolfenamic acid significantly increased the t1/2ʎz and AUC0-∞ of ceftriaxone, they significantly reduced the ClT . Ceftriaxone (40 mg/kg, IV) in concurrent use with ketoprofen and tolfenamic acid can be administrated at the 12 h dosing intervals to maintain T> minimum inhibitory concentration (MIC) values above 60% in the treatment of infections caused by susceptible pathogens with the MIC value of ≤0.75 and ≤1 µg/mL, respectively, in sheep with an inflammatory condition.

Pharmacokinetics of meloxicam, carprofen, and tolfenamic acid after intramuscular and oral administration in Japanese quails (Coturnix coturnix japonica).

The aim of this study was to determine the pharmacokinetics of meloxicam (MLX), carprofen (CRP), and tolfenamic acid (TA) in Japanese quails (Coturnix coturnix japonica) following intramuscular (IM) and oral administration at doses of 1, 10, and 2 mg/kg, respectively. A total of 72 quails were randomly divided into 3 equal groups as MLX, CRP, and TA. Each group was separated into two sub-groups that received IM and oral administration of each drug. Plasma concentrations of MLX, CRP, and TA were determined using HPLC-UV and analyzed by non-compartmental method. The t1/2ʎz and MRT of MLX, CRP, and TA after oral administration were similar to those after IM administration. The Vdarea /F of MLX, CRP, and TA after IM administration was 0.28, 2.05, and 0.20 L/kg. The Cl/F of MLX, CRP, and TA after IM administration was 0.12, 0.19, and 0.09 L/h/kg. MLX, CRP, and TA after oral administration showed significantly lower Cmax and longer Tmax compared with IM administration. The relative bioavailability of MLX, CRP, and TA following oral administration in quails was 76.13%, 61.46%, and 57.32%, respectively. The IM and oral route of MLX, CRP, and TA can be used for the treatment of various conditions in quails. However, further research is necessary to determine the pharmacodynamics and safety of MLX, CRP, and TA before use in quails.

Pharmacokinetics and bioavailability of furosemide in sheep.

The pharmacokinetics and bioavailability of furosemide were determined following intravenous (IV), intramuscular (IM), and subcutaneous (SC) administrations at 2.5 mg/kg dose in sheep. The study was conducted on six healthy sheep in a three-way, three-period, crossover pharmacokinetic design with a 15-day washout period. In first period, furosemide was randomly administered via IV to 2 sheep, IM to 2 sheep and SC to 2 sheep. In second and third periods, each sheep received furosemide via different routes of administration with the 15-day washout period. Plasma concentrations were determined using a high-performance liquid chromatography assay and analyzed by noncompartmental method. The mean total clearance and volume of distribution at steady state following IV administration were 0.24 L h-1  kg-1 and 0.17 L/kg, respectively. The elimination half-life was similar for all administration routes. The mean peak plasma concentrations of IM and SC administration were 10.33 and 3.18 µg/ml at 0.33 and 0.42 hr, respectively. The mean bioavailability of IM and SC administration was 97.91% and 37.98%, respectively. The IM injection of furosemide may be the alternative routes in addition to IV. However, further research is required to determine the effect of dose and route of administration on the clinical efficacy of furosemide in sheep.

Influences of tolfenamic acid and flunixin meglumine on the disposition kinetics of levofloxacin in sheep.

The pharmacokinetics of levofloxacin (4 mg/kg), administered both alone and in combination with tolfenamic acid (2 mg/kg) and flunixin meglumine (2.2 mg/kg), was established after intravenous administration in sheep. Plasma levofloxacin concentrations were assayed by high-performance liquid chromatography and analysed according to the two-compartment open model. Following the administration of levofloxacin alone, the mean distribution half-life, elimination half-life, total clearance, volume of distribution at steady state and area under the plasma concentration-time curve were 0.20 h, 1.82 h, 0.39 L/h/kg, 0.96 L/kg and 10.40 h × µg/mL, respectively. Tolfenamic acid and flunixin meglumine caused a slow elimination and increased plasma concentrations of levofloxacin in combination administration. Levofloxacin, with an alteration in the dosage regimen, can be used effectively with tolfenamic acid and flunixin meglumine for the therapy of infections and inflammatory conditions in sheep.

Pharmacokinetics of intravenous and intramuscular danofloxacin in red-eared slider turtles (Trachemys scripta elegans).

This study aimed to investigate the pharmacokinetics of danofloxacin in red-eared slider turtle (Trachemys scripta elegans) following a single intravenous (IV) and intramuscular (IM) administrations of 6 mg/kg, using a two-way crossover study with 30-day washout period. Eight clinically healthy red-eared slider turtle weighing 410-600 g (mean 490 g) were used for the study. Danofloxacin concentrations were measured using the reversed-phase high-performance liquid chromatography. The plasma concentration-time data were evaluated by a non-compartmental method. After IV administration, the elimination half-life (t1/2ʎz), mean residence time (MRT0-∞), area under the concentration-time curve (AUC0-∞), volume of distribution at steady state and total body clearance in plasma were 24.17 hr, 30.64 hr, 143.31 hr·µg/ml, 1.29 l/kg and 0.04 l/hr/kg, respectively. Following IM administration, t1/2ʎz, MRT0-∞, AUC0-∞, peak concentration (Cmax), time to reach Cmax, and bioavailability in plasma were 32.00 hr, 41.15 hr, 198.23 hr·µg/ml, 8.75 µg/ml, 1.5 hr and 139.89%, respectively. Danofloxacin has clinically superior pharmacokinetic properties, including the complete IM absorption, slow elimination and wide volume of distribution in red-eared slider turtles. However, further pharmacokinetics/pharmacodynamics studies are necessary for the treatment of diseases caused by susceptible bacteria with known minimum inhibitory concentration values in red-eared slider turtles.

Pharmacokinetics of ceftiofur in healthy and lipopolysaccharide-induced endotoxemic newborn calves treated with single and combined therapy.

The aim of this research was to compare plasma pharmacokinetics of ceftiofur sodium (CS) in healthy calves, and in calves with experimentally induced endotoxemia. Six calves received CS (2.2 mg/kg, IM) 2 hr after intravenous administration of 0.9% NaCl (Ceft group). After a washout period, the same 6 calves received CS 2 hr after intravenous injection of lipopolysaccharide (LPS+Ceft group). Another group of 6 calves received a combination of drug therapies that included CS 2 hr after administration of 0.9% NaCl (Comb group). A third group of 6 calves received the same combination therapy regimen 2 hr after intravenous injection of lipopolysaccharide (LPS+Comb group). Plasma concentrations of CS and all desfuroylceftiofur-related metabolites were determined using HPLC, and its pharmacokinetic properties were determined based on a two-compartment model. The peak concentration of CS in the LPS+Comb group occurred the earliest, and the clearance rate of CS was the highest in the Comb and LPS+Comb groups (P<0.05). The elimination half-life of CS in the LPS+Ceft group was longer than that in the Ceft and Comb groups (P<0.05). The results of this study indicate that combined therapies and endotoxemic status may alter the plasma pharmacokinetics of CS in calves.

Pharmacokinetics of meloxicam in red-eared slider turtles (Trachemys scripta elegans) after single intravenous and intramuscular injections.

OBJECTIVE To determine the pharmacokinetics of meloxicam after single IV and IM injections in red-eared slider turtles (Trachemys scripta elegans). ANIMALS 8 healthy red-eared slider turtles. PROCEDURES Turtles received 1 dose of meloxicam (0.2 mg/kg) IV or IM (4 turtles/route), a 30-day washout period was provided, and then turtles received the same dose by the opposite route. Blood samples were collected at predetermined times for measurement of plasma meloxicam concentration. Pharmacokinetic values for each administration route were determined with a 2-compartment open model approach. RESULTS For IV administration, mean ± SD values of major pharmacokinetic variables were 1.02 ± 0.41 hours for distribution half-life, 9.78 ± 2.23 hours for elimination half-life, 215 ± 32 mL/kg for volume of distribution at steady state, 11.27 ± 1.44 µg•h/mL for area under the plasma concentration versus time curve, and 18.00 ± 2.32 mL/h/kg for total body clearance. For IM administration, mean values were 0.35 ± 0.06 hours for absorption half-life, 0.72 ± 0.06 µg/mL for peak plasma concentration, 1.5 ± 0.0 hours for time to peak concentration, 3.73 ± 2.41 hours for distribution half-life, 13.53 ± 1.95 hours for elimination half-life, 11.33 ± 0.92 µg•h/mL for area under the plasma concentration versus time curve, and 101 ± 6% for bioavailability. No adverse reactions were detected. CONCLUSIONS AND CLINICAL RELEVANCE Long half-life, high bioavailability, and lack of immediate adverse reactions of meloxicam administered IM at 0.2 mg/kg suggested the possibility of safe and effective clinical use in turtles. Additional studies are needed to establish appropriate administration frequency and clinical efficacy.

Cardiac safety of diclofenac at a single dose in ram.

Nonsteroidal anti-inflammatory drugs are frequently prescribed drug group in human and veterinary medicine. However, diclofenac, a traditional nonsteroidal anti-inflammatory drug, related to cardiotoxicity is reported, and blood cardiac damage markers may increase within the first hours after damage. The aim of the current research was to determine the effect of diclofenac on the blood cardiac damage markers. Single dose of diclofenac (2.5 mg/kg, IM) was injected to 6 rams. Blood samples were collected in before (0 hour, control) and 6 hours after injection. Specific (troponin I, and creatine kinase-MB) and nonspecific (lactate dehydrogenase, aspartate aminotransferase) blood cardiac damage marker concentrations, routine biochemical (hepatic damage, renal damage, lipid metabolism, glucose, and phosphorus) parameters, and hemogram values were measured. Diclofenac increased (P < 0.05) specific (troponin I) and nonspecific cardiac (lactate dehydrogenase, aspartate aminotransferase), hepatic (aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase), and muscular (creatine kinase) damage markers and high density lipoprotein level, while it decreased (P < 0.05) low density lipoprotein level. Moreover, diclofenac decreased (P < 0.05) white blood cell counts and increased (P < 0.05) red blood cell counts. In conclusion, it may be stated that diclofenac shows slight cardiotoxicity, whereas it may show potent hepatic and muscular damage effects at an intramuscularly single dose in sheep. Thereby, repeated injections of diclofenac may be more harmful in sheep.

Assessment of the cardiotoxicity of tulathromycin in rabbits.

The aim of this study was to determine the cardiotoxic potency of tulathromycin. Tulathromycin (10 mg/kg, SC) was administered to ten adult male rabbits, and blood samples were obtained before and after drug administration (0 and 6 hours). Serum cardiac damage markers (troponin I, creatine kinase-MB, myoglobin, lactate dehydrogenase, aspartate aminotransferase), routine serum biochemical values (alkaline phosphatase, alanine aminotransferase, gamma-glutamyltransferase, creatinine, blood urea nitrogen, cholesterol, triglyceride, high-density lipoprotein, amylase, total protein, albumin, glucose, calcium, ionised calcium, sodium, potassium), white blood cell (WBC) and red blood cell (RBC) counts, arterial blood gas parameters (pH, partial carbon dioxide pressure, partial oxygen pressure, actual bicarbonate, standard bicarbonate, total carbon dioxide, base excess in vivo, base excess in vitro, oxygen saturation, packed cell volume, haemoglobin) and serum oxidative status (malondialdehyde, nitric oxide, superoxide dismutase, retinol, ß-carotene) were measured. Increased levels of troponin I, creatine kinase-MB and creatinine, and decreased WBC counts, ionised calcium and potassium levels were observed after drug administration. Tulathromycin treatment may cause cardiotoxicity, but its effects may be less dramatic than those of other macrolide antibiotics frequently used in veterinary medicine.

Effects of tylosin on serum cytokine levels in healthy and lipopolysaccharide-treated mice.

The effects of different doses of tylosin on serum cytokine concentrations were investigated in healthy and lipopolysaccharide-treated mice. The mice were divided into seven groups. Lipopolysaccharide (LPS) was injected into the positive control group. The other six groups received three different tylosin doses concurrently without or with LPS: 10 mg/kg, 100 mg/kg, 500 mg/kg, 10 mg/kg + LPS, 100 mg/kg + LPS and 500 mg/kg + LPS. After treatment, serum samples were collected at 0, 1, 2, 3, 6, 12 and 24 hours. Serum tumour necrosis factor alpha (TNFalpha), interleukin 1beta (IL1beta) and IL10 levels were determined by enzyme-linked immunosorbent assay (ELISA). Tylosin doses of 10 and 100 mg/kg induced no cytokine production in the healthy mice. Tylosin at 500 mg/kg had no effect on TNFalpha or IL1beta production, but it induced IL10 production in healthy mice. All doses of tylosin reduced the elevated TNFalpha and IL1beta in LPS-treated mice but increased their IL10 levels. In conclusion, these data suggest that tylosin has an immunomodulatory effect at the dose recommended for use against infection.