OBJECTIVE To determine the safety and pharmacokinetics of various doses of plant-derived cannabidiol (CBD) versus placebo following repeated oral administration. ANIMALS 20 healthy adult Beagles. PROCEDURES In a randomized, blinded, placebo-controlled trial, dogs were randomized to 5 groups balanced in body weight and sex (n = 4 dogs/group) and received a CBD (1, 2, 4, or 12 mg/kg; from cannabis extract) or placebo oil formulation PO once daily for 28 days. Outcome variables were assessed through daily health observations, veterinary examinations, CBC, and serum biochemical analysis. Blood samples were collected at various time points to estimate 24-hour pharmacokinetic profiles of CBD and selected metabolites (7-carboxy-CBD and 7-hydroxy-CBD). RESULTS Repeated CBD administration was well tolerated by dogs, with no clinically important changes in measured safety outcomes. Veterinary examinations revealed no clinically important abnormal findings. Adverse events were mild in severity. Relative to placebo administration, CBD administration at 12 mg/kg/d resulted in more gastrointestinal adverse events (mainly hypersalivation) and significantly higher serum alkaline phosphatase activity. Total systemic exposure to CBD increased on a dose-dependent basis following both acute (first dose) and chronic (28 days) administration. Within each CBD dose group, repeated administration increased total systemic exposure to CBD 1.6- to 3.3-fold. The 24-hour trough plasma CBD concentrations were also dose dependent, with a steady state reached following 2 weeks of administration. CONCLUSIONS AND CLINICAL RELEVANCE Repeated, daily oral administration of the CBD formulation led to dose-dependent increases in total systemic exposure to CBD and 24-hour trough plasma concentrations in healthy dogs. These findings could help guide dose selection.

OBJECTIVE To investigate the effects of orally administered trazodone on intraocular pressure (IOP), pupil diameter measured in the vertical plane (ie, vertical pupil diameter [VPD]), selected physical examination variables, and sedation level in healthy equids. ANIMALS 7 horses and 1 pony. PROCEDURES Food was withheld for 12 hours prior to drug administration. After baseline (time 0) sedation scoring, physical examination, and measurement of IOP and VPD, equids received 1 dose (approx 6 mg/kg) of trazodone orally. Examination and measurement procedures were repeated 0.5, 1, 2, 4, 8, 12, and 24 hours after drug administration. Blood samples were collected at each time point for analysis of plasma trazodone concentrations. Repeated-measures analysis was used to compare examination results between downstream time points and baseline. RESULTS 7 of 8 equids had mild sedation from 0.5 to 8 hours after treatment; compared with baseline values, mean IOP was significantly lower from 0.5 hours to 8 hours, mean VPD was significantly smaller at 0.5 hours, and mean rectal temperature was significantly lower from 1 to 8 hours after drug administration. Adverse effects (signs of excitement in 1 equid and sweating in 4) were self-limiting and considered minor. Mean maximum plasma concentration of trazodone was 1,493 ng/mL 0.75 hours after administration, and terminal half-life of the drug was 9.96 hours. CONCLUSIONS AND CLINICAL RELEVANCE The described oral dose of trazadone elicited sedation with a few self-limiting adverse effects in the study sample. Drug effects on IOP and VPD may alter ocular examination findings. Further investigation is warranted prior to use of trazodone for sedation in equids, particularly those with ophthalmic conditions.

OBJECTIVE To characterize the pharmacokinetics of mycophenolate mofetil (MMF) following single-dose IV or PO administration, characterize the pharmacokinetics of MMF following long-term PO administration, and describe the clinicopathologic effects of long-term MMF administration in horses. ANIMALS 12 healthy adult horses. PROCEDURES In phase 1, 6 horses received a single IV (2.5 mg/kg) or PO (5 mg/kg) dose of MMF in a randomized balanced crossover assessment (≥ 2-week interval between administrations). In phase 2, 6 other horses received MMF for 60 days (5 mg/kg, PO, q 24 h for 30 days and then 5 mg/kg, PO, q 48 h for an additional 30 days). RESULTS Following IV (single-dose) or PO (single- or multiple-dose) administration, MMF was rapidly converted to mycophenolic acid. For single-dose PO administration, mean ± SD maximum plasma mycophenolic acid concentration was 1,778.3 ± 441.5 ng/mL at 0.71 ± 0.29 hours. For single-dose IV administration, mean systemic clearance and volume of distribution at steady state were 0.689 ± 0.194 L/h/kg and 1.57 ± 0.626 L/kg, respectively. Following single doses, mean terminal half-life was 3.99 ± 0.865 hours for IV administration and 4.02 ± 1.01 hours for PO administration. The accumulation index following long-term PO administration was 1.0 ± 0.002, and the terminal half-life was 4.59 ± 1.25 hours following the final dose on day 60. None of the horses developed abnormal clinical signs or had any consistently abnormal clinicopathologic findings. CONCLUSIONS AND CLINICAL RELEVANCE Further investigation of the clinical efficacy of long-term MMF treatment of horses with autoimmune diseases is warranted.