OBJECTIVE To determine the pharmacokinetics of amantadine after oral administration of single and multiple doses to orange-winged Amazon parrots (Amazona amazonica). ANIMALS 12 adult orange-winged Amazon parrots (6 males and 6 females). PROCEDURES A single dose of amantadine was orally administered to 6 birds at 5 mg/kg (n = 2), 10 mg/kg (2), and 20 mg/kg (2) in a preliminary trial. On the basis of the results, a single dose of amantadine (10 mg/kg, PO) was administered to 6 other birds. Two months later, multiple doses of amantadine (5 mg/kg, PO, q 24 h for 7 days) were administered to 8 birds. Heart rate, respiratory rate, behavior, and urofeces were monitored. Plasma concentrations of amantadine were measured via tandem liquid chromatography–mass spectrometry. Pharmacokinetic parameter estimates were determined via noncompartmental analysis. RESULTS Mean ± SD maximum plasma concentration, time to maximum plasma concentration, half-life, and area under the concentration-versus-time curve from the last dose to infinity were 1,174 ± 186 ng/mL, 3.8 ± 1.8 hours, 23.2 ± 2.9 hours, and 38.6 ± 7.4 μg·h/mL, respectively, after a single dose and 1,185 ± 270 ng/mL, 3.0 ± 2.4 hours, 21.5 ± 5.3 hours, and 26.3 ± 5.7 μg·h/mL, respectively, at steady state after multiple doses. No adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE Once-daily oral administration of amantadine at 5 mg/kg to orange-winged Amazon parrots maintained plasma concentrations above those considered to be therapeutic in dogs. Further studies evaluating safety and efficacy of amantadine in orange-winged Amazon parrots are warranted.

OBJECTIVE To determine the pharmacokinetics of hydromorphone hydrochloride after IV and IM administration in guinea pigs (Cavia porcellus). ANIMALS 8 healthy adult guinea pigs (4 sexually intact females and 4 sexually intact males). PROCEDURES In a crossover study, hydromorphone (0.3 mg/kg) was administered once IM (epaxial musculature) or IV (cephalic catheter) to each guinea pig at a 1-week interval (2 treatments/guinea pig). Blood samples were collected before and at predetermined intervals after drug administration via a vascular access port. Plasma hydromorphone concentrations were determined by liquid chromatography–tandem mass spectrometry. Noncompartmental analysis of data was used to calculate pharmacokinetic parameters. RESULTS Mean ± SD clearance and volume of distribution for hydromorphone administered IV were 52.8 ± 13.5 mL/min/kg and 2.39 ± 0.479 L/kg, respectively. Mean residence time determined for the IV and IM administration routes was 0.77 ± 0.14 hours and 0.99 ± 0.34 hours, respectively. The maximum observed plasma concentration following IM administration of hydromorphone was 171.9 ± 29.4 ng/mL. No sedative effects were observed after drug administration by either route. CONCLUSIONS AND CLINICAL RELEVANCE Pharmacokinetic data indicated that hydromorphone at a dose of 0.3 mg/kg may be administered IV every 2 to 3 hours or IM every 4 to 5 hours to maintain a target plasma concentration between 2 and 4 ng/mL in guinea pigs. Hydromorphone had high bioavailability after IM administration. Further research is necessary to evaluate the effects of other doses and administration routes and the analgesic effects of hydromorphone in guinea pigs.

OBJECTIVE To determine the pharmacokinetics of sodium iodide (NaI) following oral administration to preweaned dairy calves, and to assess the efficacy of NaI for prevention of bovine respiratory disease (BRD) in preweaned calves at a commercial calf-raising facility. ANIMALS 434 healthy preweaned dairy calves. PROCEDURES In the first of 2 experimental trials, each of 7 calves received NaI (20 mg/kg, PO) once. Blood and nasal fluid samples were collected at predetermined times before (baseline) and for 72 hours after NaI administration for determination of iodine concentrations. Pharmacokinetic parameters were determined by noncompartmental analysis. In the second trial, 427 calves at a calf-raising facility were randomly assigned to receive NaI (20 mg/kg, PO, 2 doses 72 hours apart; n = 211) or serve as untreated controls (216). Health outcomes were compared between the 2 groups. RESULTS For all 7 calves in the pharmacokinetic trial, the iodine concentration in both serum and nasal fluid samples was significantly increased from the baseline concentration and exceeded the presumed therapeutic iodine concentration (6.35 μg/mL) throughout the sampling period. In the on-farm trial, the odds of being treated for BRD before weaning for NaI-treated calves were twice those for control calves (OR, 2.04; 95% CI, 1.38 to 3.00). CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that, although oral administration of NaI (20 mg/kg) to preweaned dairy calves achieved iodine concentrations presumed to be effective in both serum and nasal fluid, it was not effective for prevention of BRD in preweaned calves at a commercial calf-raising facility.

OBJECTIVE To describe the pharmacokinetics of morphine, lidocaine, and ketamine associated with IV administration of a constant rate infusion (CRI) of a morphine-lidocaine-ketamine (MLK) combination to calves undergoing umbilical herniorrhaphy. ANIMALS 20 weaned Holstein calves with umbilical hernias. PROCEDURES Calves were randomly assigned to receive a CRI of an MLK solution (0.11 mL/kg/h; morphine, 4.8 μg/kg/h; lidocaine, 2.1 mg/kg/h; and ketamine, 0.42 mg/kg/h) for 24 hours (MLK group) or 2 doses of flunixin meglumine (1.1 mg/kg, IV, q 24 h) and a CRI of saline (0.9% NaCl) solution (0.11 mL/kg/h) for 24 hours (control group). For all calves, the CRI was begun after anesthesia induction. Blood samples were obtained immediately before and at predetermined times for 120 hours after initiation of the assigned treatment. Noncompartmental analysis was used to estimate pharmacokinetic parameters for the MLK group. RESULTS During the CRI, steady-state serum concentrations were achieved for lidocaine and ketamine, but not morphine. Mean terminal half-life was 4.1, 0.98, and 1.55 hours and area under the concentration-time curve was 41, 14,494, and 7,426 h•μg/mL for morphine, lidocaine, and ketamine, respectively. After the CRI, the mean serum drug concentration at steady state was 6.3, 616.7, and 328 ng/mL for morphine, lidocaine, and ketamine, respectively. CONCLUSIONS AND CLINICAL RELEVANCE During the CRI of the MLK solution, steady-state serum concentrations were achieved for lidocaine and ketamine, but not morphine, likely owing to the fairly long half-life of morphine. Kinetic analyses of MLK infusions in cattle are necessary to establish optimal dosing protocols.

The endocannabinoid (eCB) system modulates the degree of injury caused by inflammation, while enhancing the activity of phagocytes that promote resolution of inflammation and tissue repair. In-vitro studies with the monoacylglycerol lipase (MAGL) inhibitor JZL184 have suggested that increased eCB signaling might enhance the ability of the host immune system to clear invading pathogens. Although the neurochemical effects of JZL184 on the eCB system in rodents are well-known, its immuneregulating effects are less clear, especially in chickens. The primary objective of this study was to explore whether modulating the eCB system affects immune responses in chickens. To do this, we administered JZL184 [10 and 40 mg/kg body weight (BW), intraperitoneal injection] into chickens prior to a challenge with avian pathogenic Escherichia coli (APEC) O78. Bacteria were isolated from livers, blood, air sacs, and hearts at 8, 28, and 56 h post-infection and the gross lesions in air sacs, livers, and hearts were also examined. Serum levels of JZL184 were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which indicated that the drug was distributed systemically. The number of birds positive for airsacculitis after APEC O78 challenge was marginally higher in groups treated with JZL184 than in the control group (P = 0.064). Rather than augmenting host defense and enhancing pathogen clearance, these results suggested that JZL184 might have immunosuppressive effects that exacerbated APEC O78 infection in chickens.

OBJECTIVE To determine the pharmacokinetics and efficacy of trazodone following rectal administration of a single dose to healthy dogs. ANIMALS 6 healthy adult dogs. PROCEDURES Each dog received a single dose of trazodone (approx 8 mg/kg) per rectum. Trazodone tablets were crushed into a powder, mixed with 5 mL of tap water, and injected into the rectum via a red rubber catheter. Sedation scores were assigned, and blood samples were collected for determination of plasma trazodone concentration at predetermined times before and after drug administration. Pharmacokinetic parameters were estimated by noncompartmental analysis. RESULTS Plasma trazodone concentration remained below the detection limit for 1 dog even though it became moderately sedate. Median (interquartile [25th to 75th percentile] range [IQR]) maximum plasma trazodone concentration and volume of distribution and clearance corrected for bioavailability were 1.00 μg/mL (0.66 to 1.40 μg/mL), 10.3 L/kg (7.37 to 14.4 L/kg), and 639 mL/kg/h (594 to 719 mL/kg/h), respectively. Median time to maximum plasma trazodone concentration and elimination half-life were 15 minutes (range, 15 to 30 minutes) and 12 hours (IQR, 7.99 to 12.7 hours), respectively. All dogs became mildly or moderately sedate, and the extent of sedation was maximal at a median of 30 minutes (IQR, 30 to 60 minutes) after trazodone administration. No adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE Rectal administration of trazodone may be a viable option for sedation and treatment of anxiety in dogs for which administration of sedatives and anxiolytics by other routes is contraindicated. Further research is necessary to better elucidate the pharmacokinetics and efficacy of trazodone following rectal administration and determine optimal dosing.

OBJECTIVE To evaluate the pharmacokinetics of hydromorphone hydrochloride after IM and IV administration to orange-winged Amazon parrots (Amazona amazonica). ANIMALS 8 orange-winged Amazon parrots (4 males and 4 females). PROCEDURES Hydromorphone (1 mg/kg) was administered once IM. Blood samples were collected 5 minutes and 0.5, 1.5, 2, 3, 6, and 9 hours after drug administration. Plasma hydromorphone concentrations were determined with liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated with a compartmental model. The experiment was repeated 1 month later with the same dose of hydromorphone administered IV. RESULTS Plasma hydromorphone concentrations were > 1 ng/mL for 6 hours in 8 of 8 and 6 of 7 parrots after IM and IV injection, respectively. After IM administration, mean bioavailability was 97.6%, and mean maximum plasma concentration was 179.1 ng/mL 17 minutes after injection. Mean volume of distribution and plasma drug clearance were 4.24 L/kg and 64.2 mL/min/kg, respectively, after IV administration. Mean elimination half-lives were 1.74 and 1.45 hours after IM and IV administration, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with rapid plasma clearance and a large volume of distribution after IV administration in orange-winged Amazon parrots. Drug elimination half-lives were short. Further pharmacokinetic studies of hydromorphone and its metabolites, including investigation of multiple doses, different routes of administration, and sustained-release formulations, are recommended.

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.

OBJECTIVE To determine the pharmacokinetics of danofloxacin following IM administration of a single dose (10 mg/kg) in koi (Cyprinus carpio). ANIMALS 69 healthy adult koi housed in a 980-L flow-through-system tank. PROCEDURES 3 fish were kept as untreated controls, and the remaining 66 fish were assigned to 11 treatment groups with 6 fish/group. Fish in the treatment groups were given a single dose of danofloxacin (10 mg/kg) IM in the left epaxial musculature. Fifteen, 30, and 45 minutes and 1, 4, 12, 24, 72, 96, 120, and 144 hours after administration of danofloxacin, fish in each treatment group were euthanized, and blood samples and samples of liver, spleen, gill, anterior kidney, posterior kidney, skin and muscle, and scales were collected. Plasma and tissue drug concentrations were determined by liquid chromatography–tandem mass spectrometry, and noncompartmental pharmacokinetic analyses were performed. Tissues from the untreated control fish and fish euthanized 144 hours after danofloxacin administration were examined histologically. RESULTS Maximum plasma concentration (mean, 8,315.7 ng/mL) was reached approximately 45 minutes after danofloxacin administration; plasma elimination half-life was 15 hours. Danofloxacin was detected in all examined tissues from all 6 fish euthanized 15 minutes after drug administration and was detected in some tissues from 3 of the 6 fish euthanized 144 hours after drug administration. For all tissues, results of histologic examination were unremarkable. CONCLUSIONS AND CLINICAL RELEVANCE IM administration of a single dose (10 mg/kg) of danofloxacin in koi resulted in rapid absorption, with maximum plasma concentration reached approximately 45 minutes after drug administration; the drug could still be detected in some tissues 144 hours after administration.