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 evaluate the effect of gadoxetic acid (contrast) dose on biliary tract enhancement, determine the optimal time after contrast injection for CT image acquisition, and assess the feasibility of CT cholangiography in sedated dogs. ANIMALS 8 healthy dogs. PROCEDURES The study had 2 parts. In part 1, 4 dogs were anesthetized and underwent CT cholangiography twice. Gadoxetic acid was administered IV at a low dose (0.025 mmol/kg) for the first procedure and high dose (0.3 mmol/kg) for the second procedure. Serial CT scans were obtained at predetermined times after contrast injection. In part 2, 4 dogs were sedated and underwent CT angiography 85 minutes after IV administration of the high contrast dose. Contrast enhancement of the biliary tract on all scans was objectively assessed by measurement of CT attenuation and qualitatively assessed by use of a subjective 4-point scoring system by 3 independent reviewers. All measurements were compared over time and between contrast doses for the dogs of part 1. Subjective measurements were compared between the sedated dogs of part 2 and anesthetized dogs of part 1. RESULTS Enhancement of the biliary tract was positively associated with contrast dose and time after contrast injection. Optimal enhancement was achieved 65 minutes after contrast injection. Subjective visualization of most biliary structures did not differ significantly between sedated and anesthetized dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated CT cholangiography with gadoxetic acid was feasible in sedated dogs. The high contrast dose provided better visualization of biliary structures than the low dose; CT scans should be obtained 65 minutes after contrast injection.

OBJECTIVE To evaluate antinociceptive effects of IV administration of hydromorphone alone or followed by buprenorphine or butorphanol to cats. ANIMALS 6 healthy adult cats. PROCEDURES In a randomized, blinded crossover design, cats received each of 4 treatments in which 2 IV injections were given 30 minutes apart: 2 of saline (0.9% NaCl) solution (Sal-Sal) or 1 each of hydromorphone HCl and saline solution (H-Sal), hydromorphone and buprenorphine HCl (H-Bupre), or hydromorphone and butorphanol tartrate (H-Butor). Skin temperature and thermal threshold were recorded before (baseline) and for 12 hours after the first injection. Percentage of maximum possible effect (%MPE) and thermal excursion (TE) were compared among treatments and measurement points. RESULTS Compared with baseline values, skin temperature was higher from 0.75 to 2 hours after the first injection for H-Sal; at 0.5, 1, 3, and 4 hours for H-Bupre; from 0.5 to 3 hours for H-Butor; and from 0.5 to 1 hours for Sal-Sal. Thermal excursion was higher than at baseline from 0.25 to 2 hours for H-Sal and H-Bupre and 0.25 to 0.75 hours for H-Butor; %MPE increased from 0.25 to 2 hours for H-Sal, 0.25 to 3 hours for H-Bupre, and 0.25 to 0.75 hours for H-Butor. Results were similar for comparisons with Sal-Sal, except TE was greater for H-Sal versus Sal-Sal and TE and %MPE were greater for H-Bupre versus Sal-Sal from 0.25 to 1 hours after the first injection. CONCLUSIONS AND CLINICAL RELEVANCE Butorphanol administration decreased the duration of antinociception achieved with hydromorphone administration in cats. This opioid interaction and its impact on pain management require additional investigation.

This study investigated the effects of ketamine and lidocaine in combination on the minimum alveolar concentration of sevoflurane (MACSEVO) in alpacas. Eight healthy, intact male, adult alpacas were studied on 2 separate occasions. Anesthesia was induced with SEVO, and baseline MAC (MACB) determination began 45 min after induction. After MACB determination, alpacas were randomly given either an intravenous (IV) loading dose (LD) and infusion of saline or a loading dose [ketamine = 0.5 mg/kg body weight (BW); lidocaine = 2 mg/kg BW] and an infusion of ketamine (25 μg/kg BW per minute) in combination with lidocaine (50 μg/kg BW per minute), and MACSEVO was re-determined (MACT). Quality of recovery, time-to-extubation, and time-to-standing, were also evaluated. Mean MACB was 1.88% ± 0.13% and 1.89% ± 0.14% for the saline and ketamine + lidocaine groups, respectively. Ketamine and lidocaine administration decreased (P < 0.05) MACB by 57% and mean MACT was 0.83% ± 0.10%. Saline administration did not change MACB. Time to determine MACB and MACT was not significantly different between the treatments. The quality of recovery, time-to-extubation, and time-to-standing, were not different between groups. The infusion of ketamine combined with lidocaine significantly decreased MACSEVO by 57% and did not adversely affect time-to-standing or quality of recovery.

OBJECTIVE To evaluate the efficacy of IV administration of a product containing hyaluronan, sodium chondroitin sulfate, and N-acetyl-d-glucosamine for prevention or treatment of osteoarthritis in horses. ANIMALS 32 healthy 2- to 5-year-old horses. PROCEDURES The study involved 2 portions. To evaluate prophylactic efficacy of the test product, horses received 5 mL of the product (n = 8) or saline (0.9% NaCl) solution (8; placebo) IV every fifth day, starting on day 0 (when osteoarthritis was induced in the middle carpal joint of 1 forelimb) and ending on day 70. To evaluate treatment efficacy, horses received either the product or placebo (n = 8/treatment) on days 16, 23, 30, 37, and 44 after osteoarthritis induction. Clinical, diagnostic imaging, synovial fluid, gross anatomic, and histologic evaluations and other tests were performed. Results of each study portion were compared between treatment groups. RESULTS Limb flexion and radiographic findings were significantly worse for horses that received the test product in the prophylactic efficacy portion than for placebo-treated horses or product-treated horses in the treatment efficacy portion. In the prophylactic efficacy portion, significantly less articular cartilage erosion was identified in product-treated versus placebo-treated horses. In the treatment efficacy portion, joints of product-treated horses had a greater degree of bone edema identified via MRI than did joints of placebo-treated horses but fewer microscopic articular cartilage abnormalities. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that caution should be used when administering the evaluated product IV to horses, particularly when administering it prophylactically, as it may have no benefit or may even cause harm.

OBJECTIVE To determine the effects of acepromazine maleate premedication on cardiovascular function before and after infusion of dobutamine hydrochloride for 30 minutes in isoflurane-anesthetized horses. ANIMALS 6 healthy adult horses. PROCEDURES Each horse was anesthetized once following premedication with acepromazine (0.02 mg/kg, IV) administered 30 minutes prior to anesthetic induction (ACP+ treatment) and once without premedication (ACP– treatment). Anesthesia was induced with IV administration of xylazine hydrochloride (0.8 mg/kg), ketamine hydrochloride (2.2 mg/kg), and diazepam (0.08 mg/kg). Horses were positioned in right lateral recumbency, and anesthesia was maintained via inhalation of isoflurane delivered in oxygen. End-tidal isoflurane concentration was adjusted to achieve a target mean arterial blood pressure of 60 mm Hg (interquartile range [25th to 75th percentile], 57 to 63 mm Hg) for at least 15 minutes. Cardiac index, oxygen delivery index, and femoral arterial blood flow indices were determined 60 minutes after anesthetic induction (baseline). Dobutamine was then infused to achieve a target mean arterial blood pressure of 80 mm Hg (interquartile range, 76 to 80 mm Hg). Data collection was repeated 30 minutes after the start of dobutamine infusion for comparison with baseline values. RESULTS Complete data sets were available from 5 of the 6 horses. Dobutamine administration resulted in significant increases in oxygen delivery and femoral arterial blood flow indices but no significant change in cardiac index for each treatment. However, at baseline or 30 minutes after the start of dobutamine infusion, findings for the ACP+ and ACP– treatments did not differ. CONCLUSIONS AND CLINICAL RELEVANCE In isoflurane-anesthetized horses, dobutamine administration increased oxygen delivery and femoral arterial blood flow indices, but these changes were unaffected by premedication with acepromazine.

OBJECTIVE To determine pharmacokinetic and pharmacodynamic properties of the novel factor Xa inhibitor apixaban in clinically normal cats. ANIMALS 5 purpose-bred domestic shorthair cats. PROCEDURES A single dose of apixaban (0.2 mg/kg, PO) was administered to each cat (time 0), and blood samples were obtained at 0, 15, 30, 45, 60, 120, 240, 360, 480, and 1,440 minutes. After a 1-week washout period, another dose of apixaban (0.2 mg/kg, IV) was administered to each cat, and blood samples were obtained at 0, 5, 10, 15, 30, 45, 60, 120, 240, 360, 480, and 1,440 minutes. Apixaban concentrations in plasma were measured via liquid chromatography–tandem mass spectrometry. Pharmacodynamic effects of apixaban were determined with a commercial assay for factor × activity, which measures endogenous factor Xa activity chromogenically. RESULTS Factor Xa was inhibited as a function of time after a single dose of apixaban administered orally or IV, and a direct inverse correlation with the plasma apixaban concentration was detected. Pharmacokinetic analysis revealed moderate clearance, short half-life, and high bioavailability for apixaban. A 2-compartment model was fit to the IV pharmacokinetic data; compartmental modeling could not be used to adequately describe the oral data because of substantial interindividual variability. CONCLUSIONS AND CLINICAL RELEVANCE Results inticated that apixaban was an effective inhibitor of factor Xa in cats. Further studies will be needed to determine pharmacokinetics and pharmacodynamics after multidose administration, effects of cardiac disease on pharmacokinetics and pharmacodynamics, dosing recommendations, and efficacy of apixaban for use in the treatment and prevention of thromboembolic disease in cats.

OBJECTIVE To monitor concentrations of sulfadimidine in the paranasal sinus mucosa (PSM) of unsedated horses following IV administration of trimethoprim-sulfadimidine via in vivo microdialysis. ANIMALS 10 healthy adult horses. PROCEDURES Concentric microdialysis probes were implanted into the subepithelial layers of the frontal sinus mucosa of standing sedated horses. Four hours after implantation, trimethoprim-sulfadimidine (30 mg/kg) was administered IV every 24 hours for 2 days; dialysate and plasma samples were collected at intervals during that 48-hour period and analyzed for concentrations of sulfadimidine. The dialysate concentration and relative loss of sulfadimidine from the perfusate were used to calculate the PSM concentration. RESULTS Microdialysis probe implantation and subsequent in vivo microdialysis were successfully performed for all 10 horses. Following the first and second administration of trimethoprim-sulfadimidine, mean ± SD peak concentrations of sulfadimidine were 55.3 ± 10.3 μg/mL and 51.5 ± 8.7 μg/mL, respectively, in plasma and 9.6 ± 4.5 μg/mL and 7.0 ± 3.3 μg/mL, respectively, in the PSM. Peak sulfadimidine concentrations in the PSM were detected at 5.9 ± 2.7 hours and 5.4 ± 2.3 hours following the first and second drug administrations, respectively. For 12 hours, mean PSM sulfadimidine concentration remained greater than the minimum inhibitory concentration indicative of sulfonamide susceptibility of equine bacterial isolates (4.75 μg/mL). CONCLUSIONS AND CLINICAL RELEVANCE In vivo microdialysis for continuous monitoring of PSM sulfadimidine concentrations in unsedated horses was feasible. Intravenous administration of trimethoprim (5 mg/kg) and sulfadimidine (25 mg/kg) proved likely to be efficient for treating sinusitis caused by highly susceptible pathogens, providing that the dosing interval is 12 hours.

OBJECTIVE To evaluate pharmacokinetics of ammonium tetrathiomolybdate (TTM) after IV and oral administration to dogs and effects of TTM administration on trace mineral concentrations. ANIMALS 8 adult Beagles and Beagle crossbreds (4 sexually intact males and 4 sexually intact females). PROCEDURES Dogs received TTM (1 mg/kg) IV and orally in a randomized crossover study. Serum molybdenum and copper concentrations were measured via inductively coupled plasma mass spectrometry in samples obtained 0 to 72 hours after administration. Pharmacokinetics was determined via noncompartmental analysis. RESULTS For IV administration, mean ± SD terminal elimination rate constant, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours−1, 4.9 ± 0.6 μg/mL, 30.7 ± 5.4 μg/mL•h, and 27.7 ± 6.8 hours, respectively. For oral administration, mean ± SD terminal elimination rate constant, time to maximum concentration, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours−1, 3.0 ± 3.5 hours, 0.2 ± 0.4 μg/mL, 6.5 ± 8.0 μg/mL•h, and 26.8 ± 8.0 hours, respectively. Oral bioavailability was 21 ± 22%. Serum copper concentrations increased significantly after IV and oral administration. Emesis occurred after IV (2 dogs) and oral administration (3 dogs). CONCLUSIONS AND CLINICAL RELEVANCE Pharmacokinetics for TTM after a single IV and oral administration was determined for clinically normal dogs. Absorption of TTM after oral administration was variable. Increased serum copper concentrations suggested that TTM mobilized tissue copper. Further studies will be needed to evaluate the potential therapeutic use of TTM in copper-associated chronic hepatitis of dogs.

Objective-To determine whether dilution of blood samples from healthy dogs with 2 hydroxyethyl starch (HES) solutions, HES 130/0.4 and HES 200/0.5, would result in platelet dysfunction as measured by closure time (Ct) beyond a dilutional effect. Sample-Citrated blood samples from 10 healthy dogs with a Ct within reference limits (52 to 86 seconds). Procedures-Blood samples were diluted 1:9 and 1:3 with 6% HES 130/0.4 and 10% HES 200/0.5 solutions and saline (0.9% NaCl) solution. Dilutions at 1:9 and 1:3 mimicked 10 mL/kg and 30 mL/kg doses, respectively, ignoring in vivo redistribution. Closure time was measured with a platelet function analyzer and compared among dilutions. Results-A dilutional effect on Ct was evident for the 1:3 dilution, compared with the 1:9 dilution, but only HES 200/0.5 increased the Ct beyond the dilutional effect at the 1:3 dilution, to a median Ct of 125 seconds (interquartile range, 117.5 to 139.5 seconds). No effect of HES or dilution on Ct was identified at the 1:9 dilution. Conclusions and Clinical Relevance-1:3 dilution of blood samples from healthy dogs with HES 200/0.5 but not HES 130/0.4 significantly increased Ct beyond the dilutional effect, suggesting that IV administration of HES 200/0.5 in dogs might cause platelet dysfunction.