Pharmacokinetics of nalbuphine administered intravenously and subcutaneously in goats (Capra aegagrus hircus).

The purpose of this study was to evaluate the pharmacokinetics (PK) of intravenously (IV) and subcutaneously (SC) administered nalbuphine in domestic goats. Nalbuphine hydrochloride was administered at 0.8 mg/kg for both IV and SC routes in six goats with a minimum of 10-day washout period between sample collection phases. Eighteen plasma samples were collected over a 36-hour period, analyzed using reverse phase high-performance liquid chromatography (HPLC). Plasma data were analyzed using compartmental and noncompartmental approaches. Following IV nalbuphine administration, elimination half-life, area under the plasma concentration time curve from time 0 to infinity (AUC0 - ∞), concentration at time zero (C0), and total body clearance were 120.4 ± 39.1 (min-1 ± SD), 17311.01 ± 7227.32 (min·ng·mL-1 ± SD), 675.6 ± 337.13 (ng·mL-1 ± SD), and 44.5 ± 13.8 (mL·min-1·kg-1 ± SD), respectively. After SC nalbuphine administration, elimination half-life, area under the plasma concentration time curve from time 0 to infinity (AUC0 - ∞), and maximum plasma drug concentration were 129 ± 52.9 (min-1 ± SD), 20826.5 ± 14376.2 (min·ng·mL-1), and 368.03 ± 503.78 (ng·mL-1). Calculated bioavailability for the SC route was 138 ± 126 (% ± SD). Nalbuphine in goats is characterized by rapid elimination and high subcutaneous bioavailability and may be a safe analgesic opioid option in goats in the future.

Pharmacokinetics and pharmacodynamics of intravenously and subcutaneously administered pantoprazole in sheep (Ovis aries).

Abomasal ulcers are recognized in sheep of all ages, but research regarding therapeutic interventions is limited. Proton Pump Inhibitors (PPIs) such as pantoprazole, are clinically used with a paucity of evidence regarding efficacy in mature sheep. Intravenous and subcutaneously administered pantoprazole dosed at 1.0 mg/kg in adult sheep will increase the pH of abomasal fluid compared to pre-administration baseline. The objectives were to assess the effect of pantoprazole, after single and multiple administration, on abomasal fluid pH in adult sheep. A third objective was to describe the pharmacokinetic parameters of IV and SC pantoprazole. Four clinically healthy adult Southdown ewes previously fitted with a gastrostomy tube in the abomasum were utilized in this randomized, 2-way cross-over trial. Ewes received pantoprazole (1.0 mg/kg) as a single and 3-dose regimen (every 24 hours). After a 10 day washout period the reverse treatment was applied. Blood for analysis of pantoprazole concentration was collected intermittently for 24 hours, and abomasal fluid pH was measured at intervals for a 96-hour period. The pH of the abomasal fluid was higher in pantoprazole treatments for up to 24 hours after dosing. Following intravenous administration of pantoprazole to study ewes, elimination half-life, volume of distribution, and clearance of pantoprazole was estimated as 3.29 hours, 0.35 L/kg, and 65.26 mL/hr/kg respectively. After subcutaneous dosing, maximum concentration, time to maximum concentration, half-life of elimination, and volume of distribution, were estimated as 2604 ng/mL, 0.55 hours, 2.48 hours, and 0.37 L/kg. Additionally, the bioavailability was estimated as 83.33%. Pantoprazole administered IV or SC may be useful for treatment or prevention of abomasal ulcers in adult sheep.

Pharmacokinetics of intraarticular liposomal amphotericin B in goats (Capra aegagrus hircus).

Lameness is a significant welfare concern in goats. Amphotericin B is used via intraarticular (IA) administration in models to study experimentally induced lameness in large animals. The main objective of this study was to estimate plasma pharmacokinetic (PK) parameters for amphotericin B in goats after a single IA administration. Liposomal amphotericin B was administered to ten Kiko-cross goats at a dose of 10 mg total (range: 0.34-0.51 mg/kg) via IA administration into the right hind lateral distal interphalangeal joint. Plasma samples were collected over 96 h. Amphotericin B concentrations were measured via liquid chromatography/mass spectrometry (LC-MS/MS). A non-compartmental analysis was used to derive PK parameters. Following single IA administration, maximum plasma concentration was estimated at 54.6 ± 16.5 ng/mL, and time to maximum concentration ranged from 6 to 12 h. Elimination half-life was estimated at 30.9 ± 16.5 h, and mean residence time was 45.1 ± 10.4 h. The volume of distribution after IA administration was 13.3 ± 9.4 L/kg. The area under the curve was 1481 ± 761 h*ng/mL. The achieved maximum concentration was less than the observed concentrations for other species and routes of administration. Further research is needed into the pharmacodynamics of IA liposomal amphotericin B in goats to determine specific research strategies.

Delayed Urethral Obstruction after Migration of a Ballistic Pellet in an Alpine Wether.

A one-year-old alpine wether was presented for emergency evaluation of stranguria. Diagnostics identified a moderately distended bladder and mild dehydration. Preliminary lateral radiographs identified two metallic structures consistent with projectile pellets in the pelvic and perineal regions and no evidence of radiopaque uroliths. A tube cystostomy was performed, and a contrast urethrogram revealed one of the pellets in the perineal region was in proximity to the urethral obstruction. Subsequent radiography and ultrasound identified the pellet as being within the lumen of the urethra. Examination of the trichotomized skin revealed two scars, including a scar over the paralumbar fossa in the region of the urinary bladder suggestive of a projectile injury. The pellet was removed by a perineal urethrotomy. The patient was able to spontaneously urinate after urethrotomy, passed a tube cystostomy challenge two weeks after surgery, and was discharged. No complications were reported. While uncommon in the veterinary and comparative medical literature, clinicians should consider the potential for projectile pellets to migrate into the urinary tract after initial injury.

Pharmacokinetics of esomeprazole in goats (Capra aegagrus hircus) after intravenous and subcutaneous administration.

Background: Stressed and hospitalized goats are at risk of developing abomasal (gastric) ulceration, but there is a paucity of pharmacokinetic studies for proton pump inhibiting drugs, such as, esomeprazole in goats. Objectives: The objectives for this study were to estimate plasma pharmacokinetic parameters for esomeprazole in adult goats after intravenous (IV) and subcutaneous (SQ) administration. A secondary objective was to describe the plasma kinetics of the metabolite esomeprazole sulfone after IV and SC administration in goats. Materials and methods: Esomeprazole was administered to 5 adult goats in a crossover study at doses of 1 mg/kg IV or 2 mg/kg SC. Plasma samples were collected over 36 h and analyzed via reverse phase HPLC to determine concentrations of esomeprazole and esomeprazole sulfone. Pharmacokinetic parameters were derived via non-compartmental analysis. Results: Following IV administration, mean values for plasma clearance (Cl), elimination half-life [T1/2 (λz)], C0, and volume of distribution (V z ) of esomeprazole were estimated at 24.9 mL/min/kg, 6 min, 2.324 µg/mL, and 0.23 L/kg, respectively. After SC administration elimination half-life, maximum concentration (Cmax) and time to maximum concentration (Tmax) of esomeprazole were estimated at 29 min, 1.038 µg/mL, and 22 minutes respectively. Maximum concentrations of the sulfone metabolite were 32 and 18 ng/mL after IV and SC administration. Conclusion: Esomeprazole was rapidly eliminated from plasma after both IV and SC injection in goats. The elimination half-life in goats appears to be shorter than reported in dogs, as well as less than that reported for pantoprazole in goats. The sulfone metabolite was detected and also rapidly eliminated from the plasma after both IV and SC administration. Additional pharmacodynamic investigations are needed to determine the efficacy of esomeprazole on abomasal (gastric) acid suppression in goats and could include larger doses or additional routes of administration.

Development of Murine Leukemia Virus Integrase-Derived Peptides That Bind Brd4 Extra-Terminal Domain as Candidates for Suppression of Acute Myeloid Leukemia.

The bromodomain and extra-terminal (BET) domain family of proteins, which include its prototypical member Brd4, is implicated in a variety of cancers and viral infections due to their interaction with cellular and viral proteins. BET proteins contain two bromodomains, a common protein motif that selectively binds acetylated lysine on histones. However, they are structurally distinct from other bromodomain-containing proteins because they encode a unique C-terminal extra-terminal (ET) domain that is important for the protein-protein interactions including jumonji C-domain-containing protein 6 (JMJD6) and histone-lysine N-methyltransferase NSD3 (NSD3). Brd4 functions primarily during transcription as a passive scaffold linking cellular and viral proteins to chromatin. The rapid development of clinical inhibitors targeting Brd4 highlights the importance of this protein as an anticancer target. Current therapeutic approaches focus on the development of small molecule acetylated lysine mimics of histone marks that block the ability of the bromodomains to bind their chromatin marks. Thus far, bromodomain-targeted agents have shown dose-limiting toxicities due to off-target effects on other bromodomain-containing proteins. Here, we exploited a viral-host protein interaction interface to design peptides for the disruption of BET protein function. A murine leukemia virus (MLV) integrase-derived peptide (ET binding motif, EBM) and its shorter minimal binding motif (pentapeptide LKIRL) were sufficient to directly bind the Brd4 ET domain and reduce cellular proliferation of an acute myeloid leukemia cell line. Using computational and biochemical approaches, we identified the minimal essential contacts between EBM and LKIRL peptides and the Brd4 ET domain. Our findings provide a structural foundation for inhibiting BET/Brd4-mediated cancers by targeting the ET domain with small peptide-based inhibitors.