Impact of lactation on pharmacokinetics of meloxicam in goats

Use of drug in lactating animal should be carefully considered due to its possibility of changes in pharmacokinetics as well as drug penetration in milk. The aim of this study was to assess the effect of lactation on pharmacokinetics of meloxicam after IV and IM administrations in goats. A crossover design (2 × 2) was used for each lactating and nonlactating group of goats with a 3-week washout period. Meloxicam (0.5 mg/kg) was administered into the jugular vein and upper gluteal muscle by IV and IM routes, respectively. The plasma and milk drug concentrations were determined by high-performance liquid chromatography with diode array detector, and the pharmacokinetic analysis was carried out by noncompartmental analysis. The pharmacokinetic parameters of meloxicam in lactating and nonlactating goats were not significantly different. The IM bioavailability of meloxicam was relatively lower in lactating (75.3 ± 18.6%) than nonlactating goats (103.8 ± 34.7%); however, the difference was not statistically significant. Moreover, AUC ratio between milk and plasma, which represent drug milk penetration, for both IV and IM administrations was less than 1 (about 0.3). In conclusion, pharmacokinetic parameters of meloxicam are not significantly altered by lactation for either the IV or IM routes of administration and this drug does not require a different dosage regimen for lactating animals.     

Pharmacokinetics of cefonicid in lactating goats after intravenous,intramuscular and subcutaneous administration,and after a long-acting formulation for subcutaneous administration

The single-dose disposition kinetics of cefonicid were determined in clinically normal lactating goats (n = 6) after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration of a conventional formulation, and after subcutaneous administration of a long-acting formulation (SC-LA). Cefonicid concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration–time data were analysed by noncompartmental pharmacokinetic methods. Steady-state volume of distribution (V_ss) and clearance (Cl) of cefonicid after IV administration were 0.14 ± 0.03 L/kg and 0.51 ± 0.07 L/h·kg, respectively. Following IM, SC and SC-LA administration, cefonicid achieved maximum plasma concentrations of 14.46 ± 0.82, 11.98 ± 1.92 and 17.17 ± 2.45 mg/L at 0.26 ± 0.13, 0.42 ± 0.13 and 0.83 ± 0.20 hr, respectively. The absolute bioavailabilities after IM, SC and SC-LA routes were 75.34 ± 11.28%, 71.03 ± 19.14% and 102.84 ± 15.155%, respectively. After cefonicid analysis from milk samples, no concentrations were found above LOQ at any sampling time. From these data, cefonicid administered at 20 mg/kg each 12 hr after SC-LA could be effective to treat bacterial infections in lactating animals not affected by mastitis problems.     

Pharmacokinetics of enrofloxacin and danofloxacin in premature calves

The aim of this study was to determine the pharmacokinetics/pharmacodynamics of enrofloxacin (ENR) and danofloxacin (DNX) following intravenous (IV) and intramuscular (IM) administrations in premature calves. The study was performed on twenty‐four calves that were determined to be premature by anamnesis and general clinical examination. Premature calves were randomly divided into four groups (six premature calves/group) according to a parallel pharmacokinetic (PK) design as follows: ENR‐IV (10 mg/kg, IV), ENR‐IM (10 mg/kg, IM), DNX‐IV (8 mg/kg, IV), and DNX‐IM (8 mg/kg, IM). Plasma samples were collected for the determination of tested drugs by high‐pressure liquid chromatography with UV detector and analyzed by noncompartmental methods. Mean PK parameters of ENR and DNX following IV administration were as follows: elimination half‐life (t_1/2λz) 11.16 and 17.47 hr, area under the plasma concentration–time curve (AUC_0‐48) 139.75 and 38.90 hr*µg/ml, and volume of distribution at steady‐state 1.06 and 4.45 L/kg, respectively. Total body clearance of ENR and DNX was 0.07 and 0.18 L hr^?1 kg^?1, respectively. The PK parameters of ENR and DNX following IM injection were t_1/2λz 21.10 and 28.41 hr, AUC_0‐48 164.34 and 48.32 hr*µg/ml, respectively. The bioavailability (F) of ENR and DNX was determined to be 118% and 124%, respectively. The mean AUC_0‐48CPR/AUC_0‐48ENR ratio was 0.20 and 0.16 after IV and IM administration, respectively, in premature calves. The results showed that ENR (10 mg/kg) and DNX (8 mg/kg) following IV and IM administration produced sufficient plasma concentration for AUC_0‐24/minimum inhibitory concentration (MIC) and maximum concentration (C_max)/MIC ratios for susceptible bacteria, with the MIC₉₀ of 0.5 and 0.03 μg/ml, respectively. These findings may be helpful in planning the dosage regimen for ENR and DNX, but there is a need for further study in naturally infected premature calves.     

Pharmacokinetic and pharmacodynamic characterization of ceftiofur crystalline‐free acid following subcutaneous administration in domestic goats

Pharmacokinetic (PK)–pharmacodynamic (PD) integration of crystalline ceftiofur‐free acid (CCFA) was established in six healthy female goats administered subcutaneously (s.c.) on the left side of the neck at a dosage of 6.6 mg/kg body weight. Serum concentrations of ceftiofur and desfuroylceftiofur (DFC) were determined using high‐performance liquid chromatography. Mutant prevention concentration (MPC), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ceftiofur were determined for Pasteurella (P.) multocida. Mean terminal half‐life and mean residence time of ceftiofur + DFC were 48.6 h and 104 h, respectively. In vitro plasma protein binding of ceftiofur was 46.6% in goats. The MIC and MBC values of ceftiofur were similar in serum and MHB and a very small difference between these values confirmed bactericidal activity of drug against P. multocida. In vitro and ex vivo time–kill curves for P. multocida demonstrated a time‐dependent killing action of drug. Considering target serum concentration of 0.20 μg/mL, PK‐PD values for AUC_24 h/MIC₉₀ and T > MIC₉₀, respectively, were 302 h and 192 h against P. multocida. A MPC/MIC ratio of 10–14 indicated that selective pressure for proliferation of resistant mutants of P. multocida is minimal after CCFA single‐dose administration. Based on MPC = 1.40 μg/mL for P. multocida, the PK‐PD indices, viz. T > MPC and AUC₂₄/MPC, were 48 h and 43 h, respectively. The data suggested the use of single dose (6.6 mg/kg, s.c.) of CCFA in goats to obtain clinical and bacteriological cure of pneumonia due to P. multocida.     

Antimicrobial resistance of Staphylococcus aureus and coagulase negative staphylococci isolated from mastitis milk samples from sheep and goats

Staphylococcus aureus and coagulase negative staphylococci (CNS) were isolated from ovine and caprine mastitis milk samples originating from more than 40 Swiss farms. CNS dominated as causal microorganisms of mastitis in small ruminants. By restriction fragment length polymorphism (RFLP) analysis of the groEL gene and sequencing of 16S rDNA, various CNS species were identified, albeit certain of them predominated. For susceptibility testing of mastitis pathogens to selected antibiotics, minimal inhibitory concentrations were determined. Of the 67 S. aureus and 208 CNS strains, 31.3 % and 8.2 % were resistant to penicillin, 29.9 % and 1.0 % to ampicillin, 1.5 % and 10.6 % to erythromycin, and 3.0 % and 7.7 % to tetracycline, respectively. Moreover, 10 CNS strains (4.8 %) were resistant to oxacillin and one CNS strain to sulfamethoxazole/trimethoprim. The results obtained describe for the first time the resistance situation of mastitis pathogens from sheep and goats in Switzerland. However, accompanying and preventing measures are also of importance in mastitis control of small ruminants.     

Pharmacokinetics of tobramycin following intravenous,intramuscular, and intra‐articular administration in healthy horses

The objectives of this study were to examine the pharmacokinetics of tobramycin in the horse following intravenous (IV), intramuscular (IM), and intra‐articular (IA) administration. Six mares received 4 mg/kg tobramycin IV, IM, and IV with concurrent IA administration (IV+IA) in a randomized 3‐way crossover design. A washout period of at least 7 days was allotted between experiments. After IV administration, the volume of distribution, clearance, and half‐life were 0.18 ± 0.04 L/kg, 1.18 ± 0.32 mL·kg/min, and 4.61 ± 1.10 h, respectively. Concurrent IA administration could not be demonstrated to influence IV pharmacokinetics. The mean maximum plasma concentration (C_max) after IM administration was 18.24 ± 9.23 μg/mL at 1.0 h (range 1.0–2.0 h), with a mean bioavailability of 81.22 ± 44.05%. Intramuscular administration was well tolerated, despite the high volume of drug administered (50 mL per 500 kg horse). Trough concentrations at 24 h were below 2 μg/mL in all horses after all routes of administration. Specifically, trough concentrations at 24 h were 0.04 ± 0.01 μg/mL for the IV route, 0.04 ± 0.02 μg/mL for the IV/IA route, and 0.02 ± 0.02 for the IM route. An additional six mares received IA administration of 240 mg tobramycin. Synovial fluid concentrations were 3056.47 ± 1310.89 μg/mL at 30 min after administration, and they persisted for up to 48 h with concentrations of 14.80 ± 7.47 μg/mL. Tobramycin IA resulted in a mild chemical synovitis as evidenced by an increase in synovial fluid cell count and total protein, but appeared to be safe for administration. Monte Carlo simulations suggest that tobramycin would be effective against bacteria with a minimum inhibitory concentration (MIC) of 2 μg/mL for IV administration and 1 μg/mL for IM administration based on C_max:MIC of 10.     

Pharmacokinetics and pharmacodynamics of intramammary cefquinome in lactating goats with and without experimentally induced Staphylococcus aureus mastitis

Values for pharmacokinetic variables are usually obtained in healthy animals, whereas drugs are frequently administered to diseased animals. This study investigated cefquinome pharmacokinetics in healthy goats and goats with experimentally induced mastitis. Five adult lactating goats received 75 mg of cefquinome intramammary infusion using a commercially available product into one udder half in healthy goats and goats with clinical mastitis that was induced by intracisternal infusion of 100 cfu of Staphylococcus aureus ATCC 29213 suspended in 5 ml of sterile culture broth. Cefquinome concentrations were determined in plasma and skimmed milk samples using high‐performance liquid chromatography (HPLC). Pharmacodynamics was investigated using the California Mastitis Test and pH of milk. Experimentally induced mastitis significantly increased the California Mastitis Test score and pH, and decreased the maximal cefquinome concentration and shortened the half‐life in milk when compared to healthy goats. In conclusion, mastitis facilitated the absorption of cefquinome from the mammary gland of lactating goats and induced marked changes in milk pH, emphasizing the importance of performing pharmacokinetic studies of antimicrobial agents in infected animals.     

Pharmacokinetics and residues in milk of oxytetracyclines administered parenterally to dairy goats

OBJECTIVE: To determine for two commercial preparations of oxytetracycline (OTC) the pharmacokinetic behaviour, the presence of detectable milk residues and the penetration in milk of OTC administered by intravenous (IV) (conventional formulation [CF]) and intramuscular (IM) routes (CF and long-acting [LA] formulations) in goats producing milk. The effects of these formulations on plasma activity values of creatine kinase (CK) and lactate dehydrogenase (LDH) were also determined as indicators of tissue damage. PROCEDURE: Five healthy lactating goats producing 1.5+/-0.5 L/d milk and weighing 56.0+/-4.8 kg were used. Single doses of OTC chlorhydrate (CF) were administered (20 mg OTC/kg) by IV (Trial 1 IV) and IM (Trial 1 IM) routes and OTC dehydrate (LA) by the IM route. The same goats were first given IV CF, then IM CF followed by IM LA with 3 weeks between each treatment. Blood and milk samples were taken. The quantification of OTC was performed by HPLC and the plasma activities of CK and LDH enzymes were determined by spectrophotometry. The presence of OTC residues in milk was determined by a commercial reagent. The plasma pharmacokinetic parameters were calculated using a two-compartment model. RESULTS: Estimates of kinetic variables following IV administration were: Vss= 400.0+/-120.0 mL/kg and CL= 110.0+/-14.0 (mL/h)/kg. The t(fi) for IV= 3.0+/-0.3 h; IM, CF = 10.5+/-2.1 h and IM, LA = 15.1+/-3.1 h. The concentration of OTC in milk at 48 h was: IV= 0.6+/-0.4; IM CF= 1.1+/-0.2 and at 72 h (IM LA)= 0.6+/-0.1 microg/mL and the penetration in milk of OTC was: IV= 70.0+/-18.0; IM CF= 79.0+/-14.0 and IM LA= 66.0+/-6.0%. The areas under the curve of CK and LDH activities in plasma were calculated by the trapezoidal method. Values of CK and LDH IM, LA were greater (P < 0.05) than those observed for IM, CF at 2 and 3 days after administration of the antibiotic. Finally, the bioavailability of OTC CF = 92.0+/-22.0 and LA= 78.0+/-23.0% was suitable for its usage by the IM route in lactating goats. CONCLUSION: Plasma concentration-time values of OTC administered parenterally in production dairy goats showed similar bioavailability for the two pharmaceutical preaprations. The presence of detectable residues in milk indicates that milk should not be used for human consumption for 2 and 3 days after administration of conventional and long-acting formulations, respectively. The increments in CK and LDH activities after the IM administration of LA are consistent with the presence of tissue damage provoked by the pharmaceutical preparations at the injection site.     

Pharmacokinetics of enrofloxacin HCl‐2H2O (ENRO‐C), PK/PD,and Monte Carlo modeling vs. Leptospira spp. in cows

The pharmacokinetics, PK/PD ratios, and Monte Carlo modeling of enrofloxacin HCl‐2H₂O (Enro‐C) and its reference preparation (Enro‐R) were determined in cows. Fifty‐four Jersey cows were randomly assigned to six groups receiving a single IM dose of 10, 15, or 20 mg/kg of Enro‐C (Enro‐C₁₀, Enro‐C₁₅, Enro‐C₂₀) or Enro‐R. Serial serum samples were collected and enrofloxacin concentrations quantified. A composite set of minimum inhibitory concentrations (MIC) of Leptospira spp. was utilized to calculate PK/PD ratios: maximum serum concentration/MIC (C_max/MIC₉₀) and area under the serum vs. time concentration of enrofloxacin/MIC (AUC_0‐24/MIC₉₀). Monte Carlo simulations targeted C_max/MIC = 10 and AUC_0‐24/MIC = 125. Mean C_max obtained were 6.17 and 2.46 μg/ml; 8.75 and 3.54 μg/ml; and 13.89 and 4.25 μg/ml, respectively for Enro‐C and Enro‐R. C_max/MIC₉₀ ratios were 6.17 and 2.46, 8.75 and 3.54, and 13.89 and 4.25 for Enro‐C and Enro‐R, respectively. Monte Carlo simulations based on C_max/MIC₉₀ = 10 indicate that only Enro‐C₁₅ and Enro‐C₂₀ may be useful to treat leptospirosis in cows, predicting a success rate ≥95% when MIC₅₀ = 0.5 μg/ml, and ≥80% when MIC₉₀ = 1.0 μg/ml. Although Enro‐C₁₅ and Enro‐C₂₀ may be useful to treat leptospirosis in cattle, clinical trials are necessary to confirm this proposal.     

Pharmacokinetic profiles of metamizole (dipyrone) active metabolites in goats and its residues in milk

Metamizole (dipyrone, MET) is a nonopioid analgesic drug commonly used in human and veterinary medicine. The aim of this study was to assess two major active metabolites of MET, 4‐methylaminoantipyrin (MAA) and 4‐aminoantipyrin (AA), in goat plasma after intravenous (IV) and intramuscular (IM) administration. In addition, metabolite concentration in milk was monitored after IM injection. Six healthy female goats received MET at a dose of 25 mg/kg by IV and IM routes in a crossover design study. The blood and milk samples were analyzed using HPLC coupled with ultraviolet detector and the plasma vs concentration curves analyzed by a noncompartmental model. In the goat, the MET rapidly converted into MAA and the mean maximum concentration was 183.97 μg/ml (at 0.08 hr) and 51.94 μg/ml (at 0.70 hr) after IV and IM administration, respectively. The area under the curve and mean residual time values were higher in the IM than the IV administered goats. The average concentration of AA was lower than MAA in both groups. Over 1 μg/ml of MAA was found in the milk (at 48 hr) after MET IM administration. In conclusion, IM is considered to be a better administration route in terms of its complete absorption with long persistence in the plasma. However, this therapeutic option should be considered in light of the likelihood of there being milk residue.     

Pharmacokinetic–pharmacodynamic relationship of marbofloxacin for Escherichia coli and Pasturella multocida following repeated intramuscular administration in goats

The pharmacokinetics (PK) and pharmacodynamics (PD) of marbofloxacin (MBF) were determined in six healthy female goats of age 1.00–1.25 years after repeated administration of MBF. The MBF was administered intramuscularly (IM) at 2 mg kg^?1 day^?1 for 5 days. Plasma concentrations of MBF were determined by high‐performance liquid chromatography, and PK parameters were obtained using noncompartmental analysis. The MBF concentrations peaked at 1 hr, and peak concentration (C_max) was 1.760 µg/ml on day 1 and 1.817 µg/ml on day 5. Repeated dosing of MBF caused no significant change in PK parameters except area under curve (AUC) between day 1 (AUC_0–∞D1 = 7.67 ± 0.719 µg × hr/ml) and day 5 (AUC_0‐∞D5 = 8.70 ± 0.857 µg × hr/ml). A slight difference in mean residence time between 1st and 5th day of administration and accumulation index (AI = 1.13 ± 0.017) suggested lack of drug accumulation following repeated IM administration up to 5 days. Minimum inhibitory concentration (MIC) demonstrated that Escherichia coli (MIC = 0.04 µg/ml) and Pasturella multocida (MIC = 0.05 µg/ml) were highly sensitive to MBF. Time‐kill kinetics demonstrated rapid and concentration‐dependent activity of MBF against these pathogens. PK/PD integration of data for E. coli and P. multocida, using efficacy indices: C_max/MIC and AUC_0–24hr/MIC, suggested that IM administration of MBF at a dose of 2 mg kg^?1 day^?1 is appropriate to treat infections caused by E. coli. However, a dose of 5 mg kg^?1 day^?1 is recommended to treat pneumonia caused by P. multocida in goats. The study indicated that MBF can be used repeatedly at dosage of 2 mg/kg in goats without risk of drug accumulation up to 5 days.     

Pharmacokinetic/pharmacodynamic evaluation of marbofloxacin as a single injection for Pasteurellaceae respiratory infections in cattle using population pharmacokinetics and Monte Carlo simulations

Population pharmacokinetic of marbofloxacin was investigated with 52 plasma concentration–time profiles obtained after intramuscular administration of Forcyl® in cattle. Animal's status, pre‐ruminant, ruminant, or dairy cow, was retained as a relevant covariate for clearance. Monte Carlo simulations were performed using a stratification by status, and 1000 virtual disposition curves were generated in each bovine subpopulation for the recommended dosage regimen of 10 mg/kg as a single injection. The probability of target attainment (PTA) of pharmacokinetic/pharmacodynamic (PK/PD) ratios associated with clinical efficacy and prevention of resistance was determined in each simulated subpopulation. The cumulative fraction of response (CFR) of animals achieving a PK/PD ratio predictive of positive clinical outcome was then calculated for the simulated dosage regimen, taking into account the minimum inhibitory concentration (MIC) distribution of Pasteurella multocida, Mannheimia haemolytica, and Histophilus somni. When considering a ratio of AUC_0‐24 hr/MIC (area under the curve/minimum inhibitory concentration) greater than 125 hr, CFRs ranging from 85% to 100% against the three Pasteurellaceae in each bovine subpopulation were achieved. The PTA of the PK/PD threshold reflecting the prevention of resistances was greater than 90% up to MPC (mutant prevention concentration) values of 1 μg/ml in pre‐ruminants and ruminants and 0.5 μg/ml in dairy cows.     

Effects of dexamethasone, levamisole, and dexamethasone-levamisole combination on neutrophil function in female goats

Effects of dexamethasone, levamisole, or combined dexamethasone-levamisole administration on polymorphonuclear neutrophil (PMN) function in healthy, adult female goats were studied. Goats were assigned to treated (n = 6) and control (n = 6) groups. In experiment 1, treated goats were given levamisole (6 mg/kg of body weight, IM). In experiment 2, treated goats were given 0.1 mg of dexamethasone/kg, IV, for 3 consecutive days, 1 mg of dexamethasone/kg, IV, for 6 consecutive days, and 6 mg of levamisole/kg, IM, with a 4th injection of 1 mg of dexamethasone/kg. All injections were administered 12 hours before blood collection. The PMN were evaluated for random migration and chemotaxis under agarose, ingestion of Staphylococcus aureus, cytochrome C reduction, iodination, and antibody-dependent cell-mediated cytotoxicity. Levamisole alone did not alter the function of caprine PMN. Both doses of dexamethasone caused increased random migration and decreased cytochrome C reduction and iodination. Dexamethasone resulted in no changes in chemotaxis, S aureus ingestion, and antibody-dependent cell-mediated cytotoxicity. Random migration and cytochrome C reduction returned toward base line in cells from dexamethasone and levamisole-treated goats. Although iodination activity in cells from dexamethasone-treated goats remained significantly (P less than 0.05) lower than those of controls after levamisole administration, a rebound toward base-line activity occurred.     

Pharmacokinetics,bioavailability and PK/PD relationship of cefquinome for Escherichia coli in Beagle dogs

The pharmacokinetics and bioavailability of cefquinome in Beagle dogs were determined by intravenous (IV), intramuscular (IM) or subcutaneous (SC) injection at a single dose of 2 mg/kg body weight (BW). The minimum inhibitory concentrations (MIC) of cefquinome against 217 Escherichia coli isolated from dogs were also investigated. After IV injection, the plasma concentration‐time curve of cefquinome was analyzed using a two‐compartmental model, and the mean values of t_1/2α (h), t_1/2β (h), V_ss (L/kg), Cl_B (L/kg/h) and AUC (μg·h/mL) were 0.12, 0.98, 0.30, 0.24 and 8.51, respectively. After IM and SC administration, the PK data were best described by a one‐compartmental model with first‐order absorption. The mean values of t_1/2Kel, t_1/2Ka, t_max (h), C_max (μg/mL) and AUC (μg·h/mL) were corresponding 0.85, 0.14, 0.43, 4.83 and 8.24 for IM administration, 0.99, 0.29, 0.72, 3.88 and 9.13 for SC injection. The duration of time that drug levels exceed the MIC (%T > MIC) were calculated using the determined MIC₉₀ (0.125 μg/mL) and the PK data obtained in this study. The results indicated that the dosage regimen of cefquinome at 2 mg/kg BW with 12‐h intervals could achieve %T > MIC above 50% that generally produced a satisfactory bactericidal effect against E. coli isolated from dogs in this study.     

Pharmacokinetics and pharmacodynamics of intravenous and transdermal flunixin meglumine in meat goats

The aim of this study was to determine the pharmacokinetics and prostaglandin E₂ (PGE₂) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight adult female Boer goats. A dose of 2.2 mg/kg was administered intravenously (IV) and 3.3 mg/kg administered TD using a cross‐over design. Plasma flunixin concentrations were measured by LC‐MS/MS. Prostaglandin E₂ concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE₂ concentrations decreased after flunixin meglumine for both routes of administration. Mean λ_z‐HL after IV administration was 6.032 hr (range 4.735–9.244 hr) resulting from a mean V_z of 584.1 ml/kg (range, 357.1–1,092 ml/kg) and plasma clearance of 67.11 ml kg^?1 hr^?1 (range, 45.57–82.35 ml kg^?1 hr^?1). The mean C_max, T_max, and λ_z‐HL for flunixin following TD administration was 0.134 μg/ml (range, 0.050–0.188 μg/ml), 11.41 hr (range, 6.00–36.00 hr), and 43.12 hr (15.98–62.49 hr), respectively. The mean bioavailability for TD flunixin was calculated as 24.76%. The mean 80% inhibitory concentration (IC₈₀) of PGE₂ by flunixin meglumine was 0.28 μg/ml (range, 0.08–0.69 μg/ml) and was only achieved with IV formulation of flunixin in this study. The PK results support clinical studies to examine the efficacy of TD flunixin in goats. Determining the systemic effects of flunixin‐mediated PGE₂ suppression in goats is also warranted.     

Pharmacokinetic and pharmacodynamic modelling of intravenous,intramuscular and subcutaneous buprenorphine in conscious cats

ObjectiveTo describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (IV), intramuscular (IM) and subcutaneous (SC) buprenorphine in cats.Study designRandomized, prospective, blinded, three period crossover experiment.AnimalsSix healthy adult cats weighing 4.1 ± 0.5 kg.MethodsBuprenorphine (0.02 mg kg^?1) was administered IV, IM or SC. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24 hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p < 0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the IV data was described using a model combining biophase equilibration and receptor association-dissociation kinetics.ResultsTT increased above baseline from 15 to 480 minutes and at 30 and 60 minutes after IV and IM administration, respectively (p < 0.05). Maximum increase in TT (mean ± SD) was 9.3 ± 4.9 °C at 60 minutes (IV), 4.6 ± 2.8 °C at 45 minutes (IM) and 1.9 ± 1.9 °C at 60 minutes (SC). TT was significantly higher at 15, 60, 120 and 180 minutes, and at 15, 30, 45, 60 and 120 minutes after IV administration compared to IM and SC, respectively. IV and IM buprenorphine concentration-time data decreased curvilinearly. SC PK could not be modeled due to erratic absorption and disposition. IV buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t_1/2k_e0 = 47.4 minutes) and receptor binding (k_on = 0.011 mL ng^?1 minute^?1). Persistence of thermal antinociception was due to slow receptor dissociation (t_1/2k_off = 18.2 minutes).Conclusions and clinical relevanceIV and IM data followed classical disposition and elimination in most cats. Plasma concentrations after IV administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the IV route should be preferred over the IM and SC routes when buprenorphine is administered to cats.     

Pharmacokinetics and selected behavioral responses to butorphanol and its metabolites in goats following intravenous and intramuscular administration

Objective To evaluate disposition of a single dose of butorphanol in goats after intravenous (IV) and intramuscular (IM) administration and to relate behavioral changes after butorphanol administration with plasma concentrations. Design Randomized experimental study. Animals Six healthy 3‐year‐old neutered goats (one male and five female) weighing 46.5 ± 10.5 kg (mean ± D). Methods Goats were given IV and IM butorphanol (0.1 mg kg^?1) using a randomized cross‐over design with a 1‐week interval between treatments. Heparinized blood samples were collected at fixed intervals for subsequent determination of plasma butorphanol concentrations using an enzyme linked immunosorbent assay (ELISA). Pharmacokinetic values (volume of distribution at steady state [Vd_SS], systemic clearance [Cl_TB], extrapolated peak plasma concentration [C₀] or estimated peak plasma concentration [C_MAX], time to estimated peak plasma concentration [T_MAX], distribution and elimination half‐lives [t_1/2], and bioavailability) were calculated. Behavior was subjectively scored. A two‐tailed paired t‐test was used to compare the elimination half‐lives after IV and IM administration. Behavioral scores are reported as median (range). A Friedman Rank Sums test adjusted for ties was used to analyze the behavioral scores. A logit model was used to determine the effect of time and concentration on behavior. A value of p < 0.05 was considered significant. Results Volume of distribution at steady state after IV administration of butorphanol was 1.27 ± 0.73 L kg^?1, and Cl_TB was 0.0096 ± 0.0024 L kg^?1 minute^?1. Extrapolated C₀ of butorphanol after IV administration was 146.5 ± 49.8 ng mL^?1. Estimated C_MAX after IM administration of butorphanol was 54.98 ± 14.60 ng mL^?1, and T_MAX was 16.2 ± 5.2 minutes; bioavailability was 82 ± 41%. Elimination half‐life of butorphanol was 1.87 ± 1.49 and 2.75 ± 1.93 hours for IV and IM administration, respectively. Goats became hyperactive after butorphanol administration within the first 5 minutes after administration. Behavioral scores for goats were significantly different from baseline at 15 minutes after IV administration and at 15 and 30 minutes after IM administration. Both time and plasma butorphanol concentration were predictors of behavior. Behavioral scores of all goats had returned to baseline by 120 minutes after IV administration and by 240 minutes after IM administration. Conclusions and Clinical Relevance The dose of butorphanol (0.1 mg kg^?1, IV or IM) being used clinically to treat postoperative pain in goats has an elimination half‐life of 1.87 and 2.75 hours, respectively. Nonpainful goats become transiently excited after IV and IM administration of butorphanol. Clinical trials to validate the efficacy of butorphanol as an analgesic in goats are needed.     

Pharmacokinetics of levosulpiride after single‐dose administration in goats (Capra hircus) by different routes of administration

Levosulpiride (LSP) is the l‐enantiomer of sulpiride, and LSP recently replacing sulpiride in several EU countries. Several studies about LSP in humans are present in the literature, but neither pharmacodynamic nor pharmacokinetic data of LSP is present for veterinary species. The aim of this study was to assess the pharmacokinetic profile of LSP after intravenous (IV), intramuscular (IM), and oral (PO) administration in goats. Animals (n = 6) were treated with 50 mg LSP by IV, IM, and PO routes according to a randomized cross‐over design (3 × 3 Latin‐square). Blood samples were collected prior and up to 24 hr after LSP administration and quantified using a validated HPLC method with fluorescence detection. IV and IM administration gave similar concentration versus time curve profiles. The IM mean bioavailability was 66.97%. After PO administration, the drug plasma concentrations were detectable only in the time range 1.5–4 hr, and the bioavailability (4.73%) was low. When the AUC was related to the administered dose in mg/kg, there was a good correlation in the IV and IM groups, but very low correlation for the PO route. In conclusion, the IM and IV administrations result in very similar plasma concentrations. Oral dosing of LSP in goats is probably not viable as its oral bioavailability was very low.     

Pharmacokinetics and ex‐vivo pharmacodynamics of cefquinome against Klebsiella pneumonia in healthy dogs

A two‐period cross‐over study was carried to investigate the pharmacokinetics (PK) and ex‐vivo pharmacodynamics (PD) of cefquinome when administrated intravenously (IV) and intramuscularly (IM) in seven healthy dogs at a dose of 2 mg/kg of body weight. Serum concentrations were determined by HPLC‐MS/MS assay and cefquinome concentration vs. time data after IV and IM were best fit to a two‐compartment open model. Cefquinome mean values of area under concentration–time curve (AUC) were 5.15 μg·h/mL for IV dose and 4.59 μg·h/mL for IM dose. Distribution half‐lives and elimination half‐lives after IV dose and IM dose were 0.27 and 0.44 h, 1.53 and 1.94 h, respectively. Values of total body clearance (Cl_B) and volume of distribution at steady‐state (V_ss) were 0.49 L·kg/h and 0.81 L/kg, respectively. After IM dose, C_max was 2.53 μg/mL and the bioavailability was 89.13%. For PD profile, the determined MIC and MBC values against K. pneumonia were 0.030 and 0.060 μg/mL in MHB and 0.032 and 0.064 μg/mL in serum. The ex vivo time‐kill curves also were established in serum. In conjunction with the data on MIC, MBC values and the ex vivo bactericidal activity in serum, the present results allowed prediction that a single cefquinome dosage of 2 mg/kg may be effective in dogs against K. pneumonia infection.     

The pathogenicity and pathogenesis of Mycoplasma capricolum subsp. capripneumoniae (F38) in the caprine mammary gland

The right mammary gland of 12 lactating goats was inoculated intracisternally with 1 ml of Mycoplasma capricolum subsp. capripneumoniae (Mcc) containing 10>⁶ colony-forming units (CFU), while their left mammary halves received 1 ml of sterile PPLO broth only. Two goats served as uninfected controls. The clinical mastitis that developed in the infected mammary halves within 24 h was initially acute but became increasingly chronic by the end of the experiment at 24 days post inoculation (DPI). The disease was characterized by atrophy of the infected mammary halves, leading to marked agalactia and an increase in somatic cell counts, with a preponderance of neutrophils initially and lymphocytes later. The Mycoplasma was re-isolated from infected mammary secretions up to 16 DPI but not from blood. Histopathology revealed that the mastitis was acute and purulent initially, followed by infiltration of lymphonuclear cells and fibroplasia in the lymphomononuclear cells and fibroplasia in the interacinar tissue, and later by massive fibrosis. Immunohistology demonstrated the presence of Mycoplasma-like bodies localized mainly on the surface of acinar/duct epithelial cells. The studies showed that Mcc was highly pathogenic in the caprine mammary gland.