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ABSTRACT:The goal of this study was to establish an easy-to-perform, reliable, and safe protocol for intraperitoneal injection anaesthesia in rats, as well as an easy method to assess anaesthesia depth under routine clinical conditions. Seventy Wistar rats (35 males and 35 females) were used to evaluate intraperitoneal anaesthesia with ketamine (75 mg/kg) combined with one of the following central nervous system depressors: acepromazine (2.5 mg/kg), diazepam (5 mg/kg), medetomidine (0.5 mg/kg), midazolam (5 mg/kg) and xylazine (2.5 mg/kg). Significant differences were found between the combinations in ataxia, recovery and righting parameters, as well as respiratory and heart rates and haemoglobin saturation by oxygen, whereas significant differences between sexes for the parameters of ataxia, hypnosis, recovery, righting and exploratory behaviour were observed upon waking. The best results for parameters such as induction, and maintenance and recovery from anaesthesia (more regular and stable) were observed with α 2 -agonists: ketamine/xylazine in males and ketamine/medetomidine in females.

BackgroundBacterial pneumonia in goats is usually caused by Mannheimia haemolytica and Pasteurella multocida. Another important infection disease in lactating goats is intramammary infection producing mastitis, usually associated with coagulase-negative Staphylococcus spp. However, treatment of bacterial pneumonia in goats not affected by mastitis problems should be restricted to antimicrobials with scant penetration to milk in order to avoid long withdrawal times. Ceftiofur is a third-generation cephalosporin antimicrobial with activity against various gram-positive and gram-negative, aerobic and anaerobic bacteria encountered by domestic animals. The objectives of the present study were to establish the serum concentration–time profile for ceftiofur in lactating goats after intravenous, subcutaneous and a SC-long-acting ceftiofur formulation; to determine ceftiofur penetration into milk; to determine in vitro and ex vivo activity of ceftiofur establishing MIC, MBC, MPC and time-kill profiles against field strains of M. haemolytica and finally to calculate the main surrogate markers of efficacy.ResultsThe pharmacokinetics studies revealed an optimal PK properties for the SC-LA formulation tested. Ceftiofur was well absorbed following SC and SC-LA administration, with absolute bioavailabilities (F) of 85.16 and 84.43 %, respectively. After ceftiofur analysis from milk samples, no concentrations were found at any sampling time. The MIC, MBC and MPC data of ceftiofur against five M. haemolytica strains isolated from goats affected by pneumonia were tested showing excelent sensitivity of ceftiofur against this pathogen. For PK-PD analysis, ratios were calculated suggesting a high level of bacterial kill against the five strains of M. haemolytica tested.ConclusionsThe systemic ceftiofur exposure achieved in lactating goats following IV, SC and especially with the SC-LA administration is consistent with the predicted PK-PD ratios needed for a positive therapeutic outcome for M. haemolytica. Subcutaneous administration of the long-acting formulation showed safety and tolerance for all the animals used. Ceftiofur concentrations exceeded the MIC and MBC for up to 72 h and MPC for up 32 h in serum. Thus, this drug could be effective in treating infectious diseases of goats caused by M. haemolytica at a dose of 6 mg/kg with the SC-LA formulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-016-0863-9) contains supplementary material, which is available to authorized users.

Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of veterinary fluoroquinolones as enrofloxacin, its metabolite ciprofloxacin, danofloxacin, difloxacin and marbofloxacin against strains (n=24) isolated from milk of sheep and goats affected by clinical mastitis were evaluated. The authors have used the MIC and MPC, as well as the pharmacokinetic-pharmacodynamic relationships in plasma and milk. MIC values were significantly different between drugs, unlike MPC values. Lower MIC values were obtained for danofloxacin and difloxacin, middle and higher values for enrofloxacin, ciprofloxacin and marbofloxacin. However, differences in MPC values were not found between drugs. At conventional doses, the AUC/MIC and AUC/MPC ratios were close to 30-80 hours and 5-30 hours, with exception of danofloxacin, in plasma and milk. The time inside the mutant selection window (T) was close to 3-6 hours for enrofloxacin, ciprofloxacin and marbofloxacin, near to 8 hours for danofloxacin and 12-22 hours for difloxacin. From these data, the mutant selection window could be higher for danofloxacin and difloxacin compared with the other fluoroquinolones tested. The authors concluded that enrofloxacin and marbofloxacin, at conventional doses, could prevent the selection of bacterial subpopulations of , unlike danofloxacin and difloxacin, where higher doses could be used.

BackgroundIntravenous pharmacokinetics and oral bioavailability of cannabidiol (CBD) with different formulations have not been investigated in horses and may represent a starting point for clinical studies.ObjectivesTo describe pharmacokinetics after intravenous and oral administrations with oil and micellar formulations and simulate different treatments.Study designSingle intravenous experiment and two‐way randomised oral experiments, Latin‐square design.MethodsEight healthy horses received intravenous CBD at 1.00 mg/kg dose, oral CBD in sesame oil and in micellar formulation, both at 10.00 mg/kg. Concentrations were measured using LC–MS/MS and fitted by nonlinear mixed effect modelling. Parameters obtained were used to simulate single and multiple treatments at steady state.ResultsIntravenous and oral concentrations were simultaneously fitted using a three‐compartment model. Final estimates indicate that CBD has a volume of distribution of 36 L/kg associated with a systemic clearance of 1.46 L/h/kg and half‐lives ranged between 24 and 34 h. Oral bioavailability was close to 14% for both oral administrations. Simulated dose regimen of CBD every 12 and 24 h predicted similar percentages to reach effective plasma concentration with both oral formulation at 10.00 mg/kg.Main limitationsA small horse population was used (8 horses per trial).Conclusions and clinical importanceOral bioavailability was low at the doses studied but fell within the range described for horse and other species. CBD had a high steady‐state volume of distribution, a high clearance and long half‐lives. No adverse reactions were detected at any dose or route. The micellar formulation showed a faster absorption and higher concentration peak, while the oil formulation presented lower levels, but more maintained over time. Simulations predicted that both could be useful in multiple oral dose treatments. These results indicated that CBD could be of interest, but further studies are needed to evaluate its clinical use in horses.

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Contagious agalactia is a mycoplasmosis affecting small ruminants that have become an important issue in many countries. However, PK/PD studies of antibiotics to treat this problem in lactating goats affected by Mycoplasma (M.) agalactiae, the main CA-causing mycoplasma are almost non-existent. The aims of this study were to evaluate the plasma and milk disposition of marbofloxacin in lactating goats after intravenous (IV), subcutaneous (SC) and subcutaneous poloxamer P407 formulations with and without carboxy-methylcellulose (SC-P407-CMC and SC-P407) administration. Marbofloxacin concentrations were analysed by the High Performance Liquid Chromatography (HPLC) method. Minimum inhibitory concentrations (MIC) of M. agalactiae field isolates from mastitic goat’s milk were used to calculate surrogate markers of efficacy. Terminal half-lives of marbofloxacin after IV, SC, SC-P407 and SC-P407-CMC administration were 7.12, 6.57, 13.92 and 12.19 h in plasma, and the half-lives of elimination of marbofloxacin in milk were 7.22, 7.16, 9.30 and 7.74 h after IV, SC, SC-P407 and SC-P407-CMC administration, respectively. Marbofloxacin penetration from the blood into the milk was extensive, with Area Under the Curve (AUCmilk/AUCplasma) ratios ranged 1.04–1.23, and maximum concentrations (Cmax-milk/Cmax-plasma) ratios ranged 0.72–1.20. The PK/PD surrogate markers of efficacy fAUC24/MIC and the Monte Carlo simulation show that marbofloxacin ratio (fAUC24/MIC > 125) using a 90% of target attainment rate (TAR) need a dose regimen between 8.4 mg/kg (SC) and 11.57 mg/kg (P407CMC) and should be adequate to treat contagious agalactia in lactating goats.

Background Nonsteroidal anti‐inflammatory drugs are administered in horses for several systemic diseases. Selective cyclooxygenase‐2 inhibitors are preferred because of lower risk of adverse effects. Several meloxicam formulations have been tested in horses, but a recently marketed granule oral formulation has not been studied. Objective To characterize the pharmacokinetics of a novel granule meloxicam formulation in fasted and fed horses, and to compare pharmacokinetic features with oral suspension and tablets. Animals Seven healthy adult horses. Methods Meloxicam was administered at 0.6 mg/kg in fasted or fed horses. Blood samples were collected for pharmacokinetic analysis, and vital signs, hematology, and biochemistry variables were monitored for 72 hours. Results No adverse effects were detected. Volume of distribution and clearance after intravenous administration of meloxicam were 0.36 L/kg and 29.12 mL/h/kg, respectively, with a 12.39 hours of terminal half‐life. Protein binding was of 97%. Bioavailability was high for every oral formulation, ranging 70%‐110%, without feed effect. Because of a slower absorption, meloxicam after administration of granules had a longer half‐life (24 and 34 hours, fasted and fed, respectively) and mean residence time (31 and 47 hours), than suspension and tablets (ranging 10‐13 and 13‐15 hours, respectively). In addition, the time above therapeutic concentration was higher for the granule formulation than other formulations. Conclusions and Clinical Importance Granule formulation has different PK parameters compared to other oral formulations, which could enable this formulation to be used for different dosage regimens in order to reach a desired clinical effect or decrease the risk of adverse effects.