Diminazene aceturate is one of a limited number of drugs currently being used in animals to treat the tsetse fly-transmitted protozoal disease, African trypanosomiasis. Efficacy of the drug at the recommended single IM administered doses of 3.5 and 7.0 mg/kg of body weight is widely acknowledged. However, resistance to the drug at these dosages has been reported. Although the mechanisms of resistance to diminazene are poorly understood, field and experimental data indicate that it may develop naturally through administration of subcurative doses, or as a result of cross-resistance. Evidence from other experimental studies indicates that there are additional mechanisms by which trypanosomes may develop resistance to diminazene aceturate. For instance, some populations ot Trypanosoma brucei and T. vivax are refractory to treatment because of their ability to invade the CNS, a site that is believed to be poorly accessible to diminazene. Furthermore, in recent studies carried out in goats, it has been documented that the ability of T. Congolense IL 3274 to survive treatment with diminazene depends on the stage of infection when treatment is administered; populations of the parasite reappeared in animals that were treated on day 19 after tsetse fly challenge, whereas all goats were cured when treated on day 1 of infection. Because trypanosomes are confined to the skin on day 1 after infection, but thereafter invade the blood circulation, it is possible that the efficacy of the treatment on day 1 is attributable to exposure of the small number of parasites, relative to later stages of infection, to higher concentrations of drug than those attained in blood. The objective of the study reported here was to determine whether diminazene's pharmacokinetics differ between plasma and lymph draining the skin of goats and therefore account for the variation in therapeutic activity of the drug at different stages of a tsetse fly-transmitted infection. Peripheral lymph was used for this work because it appears to be identical in composition to tissue interstitial fluid, into which trypanosomes are inoculated by infected tsetse flies when feeding.

Introduction: The objective of this study was to describe a pharmacokinetic–pharmacodynamic (PK/PD) approach for determination of a rational dosage of ampicillin (AMP) and depletion of the antibiotic residues in milk after intramammary administration to cows.Material and Methods: The cows came from different farms from the Lublin Province area. They (n = 9) received 5 g of the drug, containing 75 mg of AMP sodium in physiological solution, through a syringe tube by intramammary administration. Following single intramammary administration, the milk samples (5 mL) were collected after 2, 4, 6, 8, 10, 24, 36, 48, and 60 h. The liquid chromatography-mass spectrometry analysis was performed on the Agilent 1200 system connected to an AB Sciex API 4000™ mass spectrometer. The pharmacokinetic analysis of the concentrations of the antibiotic in milk was performed using software Phoenix® WinNonlin® 6.4. Calculations were made in non-compartmental (slopes, highest, amounts, and moments) and compartmental analysis.Results: The pharmacokinetic characteristics of AMP after intramammary administration indicate rapid elimination of the drug from milk. The mean residence time had a several-fold lower value than the designated elimination half-life and amounts to only 3.4 h. The concentration of the drug in the milk dropped relatively quickly and the process was very dynamic.Conclusion: The conducted research confirms the rationale of using the PK/PD model in order to verify the dosing regimen for other antibiotic groups and various indicators of the applied PK/PD model.

OBJECTIVE To determine the pharmacokinetics and adverse effects of maropitant citrate after IV and SC administration to New Zealand White rabbits (Oryctolagus cuniculus). ANIMALS 11 sexually intact (3 males and 8 females) adult rabbits. PROCEDURES Each rabbit received maropitant citrate (1 mg/kg) IV or SC. Blood samples were collected at 9 (SC) or 10 (IV) time points over 48 hours. After a 2-week washout period, rabbits received maropitant by the alternate administration route. Pharmacokinetic parameters were calculated. Body weight, food and water consumption, injection site, mentation, and urine and fecal output were monitored. RESULTS Mean ± SD maximum concentration after SC administration was 14.4 ± 10.9 ng/mL and was detected at 1.25 ± 0.89 hours. Terminal half-life after IV and SC administration was 10.4 ± 1.6 hours and 13.1 ± 2.44 hours, respectively. Bioavailability after SC administration was 58.9 ± 13.3%. Plasma concentration at 24 hours was 2.87 ± 1.69 ng/mL after IV administration and 3.4 ± 1.2 ng/mL after SC administration. Four rabbits developed local dermal reactions at the injection site after SC injection. Increased fecal production was detected on the day of treatment and 1 day after treatment. CONCLUSIONS AND CLINICAL RELEVANCE Plasma concentrations of rabbits 24 hours after SC and IV administration of maropitant citrate (1 mg/kg) were similar to those of dogs at 24 hours. Reactions at the SC injection site were the most common adverse effect detected. Increased fecal output may suggest an effect on gastrointestinal motility. Additional pharmacodynamic and multidose studies are needed.

OBJECTIVE To evaluate the pharmacokinetics and pharmacodynamics of naloxone hydrochloride in dogs following intranasal (IN) and IV administration. ANIMALS 6 healthy adult mixed-breed dogs. PROCEDURES In a blinded crossover design involving 2 experimental periods separated by a washout period (minimum of 7 days), dogs were randomly assigned to receive naloxone IN (4 mg via a commercially available fixed-dose naloxone atomizer; mean ± SD dose, 0.17 ± 0.02 mg/kg) or IV (0.04 mg/kg) in the first period and then the opposite treatment in the second period. Plasma naloxone concentrations, dog behavior, heart rate, and respiratory rate were evaluated for 24 hours/period. RESULTS Naloxone administered IN was well absorbed after a short lag time (mean ± SD, 2.3 ± 1.4 minutes). Mean maximum plasma concentration following IN and IV administration was 9.3 ± 2.5 ng/mL and 18.8 ± 3.9 ng/mL, respectively. Mean time to maximum concentration following IN administration was 22.5 ± 8.2 minutes. Mean terminal half-life after IN and IV administration was 47.4 ± 6.7 minutes and 37.0 ± 6.7 minutes, respectively. Mean bioavailability of naloxone administered IN was 32 ± 13%. There were no notable changes in dog behavior, heart rate, or respiratory rate following naloxone administration by either route. CONCLUSIONS AND CLINICAL RELEVANCE Use of a naloxone atomizer for IN naloxone administration in dogs may represent an effective alternative to IV administration in emergency situations involving opioid exposure. Future studies are needed to evaluate the efficacy of IN naloxone administration in dogs with opioid intoxication, including a determination of effective doses.

OBJECTIVE To determine the pharmacokinetics and sedative effects of 2 doses of a concentrated buprenorphine formulation after SC administration to red-tailed hawks (Buteo jamaicensis). ANIMALS 6 adult red-tailed hawks. PROCEDURES Concentrated buprenorphine (0.3 mg/kg, SC) was administered to all birds. Blood samples were collected at 10 time points over 24 hours after drug administration to determine plasma buprenorphine concentrations. After a 4-week washout period, the same birds received the same formulation at a higher dose (1.8 mg/kg, SC), and blood samples were collected at 13 time points over 96 hours. Hawks were monitored for adverse effects and assigned agitation-sedation scores at each sample collection time. Plasma buprenorphine concentrations were quantified by liquid chromatography–tandem mass spectrometry. RESULTS Mean time to maximum plasma buprenorphine concentration was 7.2 minutes and 26.1 minutes after administration of the 0.3-mg/kg and 1.8-mg/kg doses, respectively. Plasma buprenorphine concentrations were > 1 ng/mL for mean durations of 24 and 48 hours after low- and high-dose administration, respectively. Mean elimination half-life was 6.23 hours for the low dose and 7.84 hours for the high dose. Mean agitation-sedation scores were higher (indicating some degree of sedation) than the baseline values for 24 hours at both doses. No clinically important adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE Concentrated buprenorphine was rapidly absorbed, and plasma drug concentrations considered to have analgesic effects in other raptor species were maintained for extended periods. Most birds had mild to moderate sedation. Additional studies are needed to evaluate the pharmacodynamics of these doses of concentrated buprenorphine in red-tailed hawks.

OBJECTIVE To evaluate the plasma disposition of mycophenolic acid (MPA) and its derivatives MPA glucuronide and MPA glucoside after twice-daily infusions of mycophenolate mofetil (MMF) in healthy cats for 3 days and to assess the effect of MMF administration on peripheral blood mononuclear cell (PBMC) counts and CD4+-to-CD8+ ratios. ANIMALS 5 healthy adult cats. PROCEDURES MMF was administered to each cat (10 mg/kg, IV, q 12 h for 3 days). Each dose of MMF was diluted with 5% dextrose in water and then administered over a 2-hour period with a syringe pump. Blood samples were collected for analysis. A chromatographic method was used to quantitate concentrations of MPA and its metabolites. Effects of MMF on PBMC counts and CD4+-to-CD8+ ratios were assessed by use of flow cytometry. RESULTS All cats biotransformed MMF into MPA. The MPA area under the plasma concentration–time curve from 0 to 14 hours ranged from 14.6 to 37.6 mg·h/L and from 14.4 to 22.3 mg·h/L after the first and last infusion, respectively. Total number of PBMCs was reduced in 4 of 5 cats (mean ± SD reduction, 25.9 ± 15.8% and 26.7 ± 19.3%) at 24 and 48 hours after the end of the first infusion of MMF, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Plasma disposition of MPA after twice-daily IV infusions for 3 days was variable in all cats. There were no remarkable changes in PBMC counts and CD4+-to-CD8+ ratios.

OBJECTIVE To measure concentrations of trazodone and its major metabolite in plasma and urine after administration to healthy horses and concurrently assess selected physiologic and behavioral effects of the drug. ANIMALS 11 Thoroughbred horses enrolled in a fitness training program. PROCEDURES In a pilot investigation, 4 horses received trazodone IV (n = 2) or orally (2) to select a dose for the full study; 1 horse received a vehicle control treatment IV. For the full study, trazodone was initially administered IV (1.5 mg/kg) to 6 horses and subsequently given orally (4 mg/kg), with a 5-week washout period between treatments. Blood and urine samples were collected prior to drug administration and at multiple time points up to 48 hours afterward. Samples were analyzed for trazodone and metabolite concentrations, and pharmacokinetic parameters were determined; plasma drug concentrations following IV administration best fit a 3-compartment model. Behavioral and physiologic effects were assessed. RESULTS After IV administration, total clearance of trazodone was 6.85 ± 2.80 mL/min/kg, volume of distribution at steady state was 1.06 ± 0.07 L/kg, and elimination half-life was 8.58 ± 1.88 hours. Terminal phase half-life was 7.11 ± 1.70 hours after oral administration. Horses had signs of aggression and excitation, tremors, and ataxia at the highest IV dose (2 mg/kg) in the pilot investigation. After IV drug administration in the full study (1.5 mg/kg), horses were ataxic and had tremors; sedation was evident after oral administration. CONCLUSIONS AND CLINICAL RELEVANCE Administration of trazodone to horses elicited a wide range of effects. Additional study is warranted before clinical use of trazodone in horses can be recommended.

OBJECTIVE To assess rheological properties and in vitro diffusion of poloxamer 407 (P407) and butorphanol-P407 (But-P407) hydrogels and to develop a sustained-release opioid formulation for use in birds. SAMPLE P407 powder and a commercially available injectable butorphanol tartrate formulation (10 mg/mL). PROCEDURES P407 and But-P407 gels were compounded by adding water or butorphanol to P407 powder. Effects of various concentrations of P407 (20%, 25% and 30% [{weight of P407/weight of diluent} × 100]), addition of butorphanol, and sterilization through a microfilter on rheological properties of P407 were measured by use of a rheometer. In vitro diffusion of butorphanol from But-P407 25% through a biological membrane was compared with that of a butorphanol solution. RESULTS P407 20% and 25% formulations were easily compounded, whereas it was difficult to obtain a homogenous P407 30% formulation. The P407 was a gel at avian body temperature, although its viscosity was lower than that at mammalian body temperature. The But-P407 25% formulation (butorphanol concentration, 8.3 mg/mL) was used for subsequent experiments. Addition of butorphanol to P407 as well as microfiltration did not significantly affect viscosity. Butorphanol diffused in vitro from But-P407, and its diffusion was slower than that from a butorphanol solution. CONCLUSIONS AND CLINICAL RELEVANCE But-P407 25% had in vitro characteristics that would make it a good candidate for use as a sustained-release analgesic medication. Further studies are needed to characterize the pharmacokinetic and pharmacodynamic properties of But-P407 25% in vivo before it can be recommended for use in birds.

OBJECTIVE To determine whether target values for pharmacokinetic-pharmacodynamic (PK-PD) indices against selected canine pathogens were achievable for pradofloxacin in various canine fluids and leukocytes. ANIMALS 8 healthy adult hounds (experiments 1 and 2) and 6 healthy adult dogs (experiment 3). PROCEDURES In 3 experiments, pradofloxacin (3, 6, or 12 mg/kg) and enrofloxacin (5 or 10 mg/kg) were orally administered once a day for 5 days, and blood, interstitial fluid (ISF), and other fluid samples were collected at various points. Sample drug concentrations were measured, and noncompartmental pharmacokinetic analysis was performed; then, PK-PD indices (ratios between maximum observed concentration [Cmax] and minimum inhibitory or mutant prevention concentrations) were determined for 7 bacterial species. RESULTS PK-PD values for pradofloxacin at 3 mg/kg were approximately 5 times as high in leukocyte versus plasma and were lowest in CSF, synovial fluid, and aqueous humor. No significant differences were noted between serum and ISF. Value ratios for serum versus other body fluids were numerically higher for pradofloxacin (vs enrofloxacin) for all fluid types except CSF and aqueous humor. Target PK-PD values were exceeded for pradofloxacin against all 7 bacterial species in leukocytes and against all species except Bacteroides spp in serum and ISF. Enrofloxacin achieved the target Cmax-to-minimum inhibitory concentration ratio against Pasteurella multocida in serum, ISF, and leukocytes and for Staphylococcus pseudintermedius in serum and leukocytes. A Cmax-to-mutant prevention concentration ratio ≥ 1 against Eschericha coli was achieved for pradofloxacin at 6 mg/kg. CONCLUSIONS AND CLINICAL RELEVANCE These findings supported once-daily oral administration of pradofloxacin to dogs at the currently recommended dose (7.5 mg/kg).

OBJECTIVE To determine the effects of coadministration of naltrexone, a human opioid abuse deterrent, on the pharmacokinetics and pharmacodynamics of a methadone-fluconazole combination administered orally to dogs. Animals: 12 healthy Beagles. PROCEDURES Dogs (body weight, 10.7 to 13.9 kg) were randomly allocated to 2 groups in a parallel design study. All dogs received fluconazole (100 mg [7.19 to 9.35 mg/kg], PO). Twelve hours later (time 0), dogs were administered methadone (10 mg [0.72 to 0.93 mg/kg]) plus fluconazole (50 mg [3.62 to 4.22 mg/kg]; methadone-fluconazole) or methadone (10 mg [0.72 to 0.93 mg/kg]) plus fluconazole (50 mg [3.60 to 4.67 mg/kg]) and naltrexone (2.5 mg [0.18 to 0.23 mg/kg]; methadone-fluconazole-naltrexone), PO, in a gelatin capsule. Blood samples were collected for pharmacokinetic analysis, and rectal temperature and sedation were assessed to evaluate opioid effects at predetermined times up to 24 hours after treatment. RESULTS Most dogs had slight sedation during the 12 hours after drug administration; 1 dog/group had moderate sedation at 1 time point. Mean rectal temperatures decreased significantly from baseline (immediate pretreatment) values from 2 to ≥ 12 hours and 2 to ≥ 8 hours after methadone-fluconazole and methadone-fluconazole-naltrexone treatment, respectively. Geometric mean maximum observed concentration of methadone in plasma was 35.1 and 33.5 ng/mL and geometric mean terminal half-life was 7.92 and 7.09 hours after methadone-fluconazole and methadone-fluconazole-naltrexone treatment, respectively. Naltrexone was sporadically detected in 1 dog. The active naltrexone metabolite, β-naltrexol, was not detected. The inactive metabolite, naltrexone glucuronide, was detected in all dogs administered methadone-fluconazole-naltrexone. CONCLUSIONS AND CLINICAL RELEVANCE Opioid effects were detected after oral administration of methadone-fluconazole or methadone-fluconazole-naltrexone. Further studies assessing additional opioid effects, including antinociception, are needed.