Objective-To determine and compare the ratio of uracil (U) to dihydrouracil (UH2) concentrations in plasma as an indicator of dihydropyrimidine dehydrogenase activity in clinically normal dogs and dogs with neoplasia or renal insufficiency. Animals-101 client-and shelter-owned dogs. Procedures-Study dogs included 74 clinically normal dogs, 17 dogs with neoplasia, and 10 dogs with renal insufficiency. For each dog, a blood sample was collected into an EDTA-containing tube; plasma U and UH2 concentrations were determined via UV high-performance liquid chromatography, and the U:UH2 concentration ratio was calculated. Data were compared among dogs grouped on the basis of sex, clinical group assignment, reproductive status (sexually intact, spayed, or castrated), and age. Results-Mean +/- SEM U:UH2 concentration ratio for all dogs was 1.55 +/- 0.08 (median, 1.38; range, 0.4 to 7.14). In 14 (13.9%) dogs, the U:UH2 concentration ratio was considered abnormal (ie, > 2). Overall, mean ratio for sexually intact dogs was significantly higher than that for neutered dogs; a similar difference was apparent among males but not females. Dogs with ratios > 2 and dogs with ratios less than 2 did not differ significantly with regard to sex, clinical group, reproductive status, or age. Conclusions and Clinical Relevance-Determination of the U:UH2 concentration ratio was easy to perform. Ratios were variable among dogs, possibly suggesting differences in dihydropyrimidine dehydrogenase activity. However, studies correlating U:UH2 concentration ratio and fluoropyrimidine antimetabolite drug tolerability are required to further evaluate the test's validity and its appropriate use in dogs.

Objective: To evaluate the use of midazolam, ketamine, and xylazine for total IV anesthesia (TIVA) in horses. Animals: 6 healthy Thoroughbred mares. Procedures: Horses were sedated with xylazine (1.0 mg/kg, IV). Anesthesia was induced with midazolam (0.1 mg/kg, IV) followed by ketamine (2.2 mg/kg, IV) and was maintained with an IV infusion of midazolam (0.002 mg/kg/min), ketamine (0.03 mg/kg/min), and xylazine (0.016 mg/kg/min). Horses underwent surgical manipulation and injection of the palmar digital nerves; duration of the infusion was 60 minutes. Additional ketamine (0.2 to 0.4 mg/kg, IV) was administered if a horse moved its head or limbs during procedures. Cardiopulmonary and arterial blood variables were measured prior to anesthesia; at 10, 20, 30, 45, and 60 minutes during infusion; and 10 minutes after horses stood during recovery. Recovery quality was assessed by use of a numeric (1 to 10) scale with 1 as an optimal score. Results: Anesthesia was produced for 70 minutes after induction; supplemental ketamine administration was required in 4 horses. Heart rate, respiratory rate, arterial blood pressures, and cardiac output remained similar to preanesthetic values throughout TIVA. Arterial partial pressure of oxygen and oxygen saturation of arterial hemoglobin were significantly decreased from preanesthetic values throughout anesthesia; oxygen delivery was significantly decreased at 10- to 30-minute time points. Each horse stood on its first attempt, and median recovery score was 2. Conclusions and Clinical Relevance: Midazolam, ketamine, and xylazine in combination produced TIVA in horses. Further studies to investigate various dosages for midazolam and ketamine or the substitution of other α2-adrenoceptor for xylazine are warranted.

Objective: To determine plasma pharmacokinetics of penciclovir following oral and rectal administration of famciclovir to young Asian elephants (Elephas maximus). Animals: 6 healthy Asian elephants (5 females and 1 male), 4.5 to 9 years old and weighing 1,646 to 2,438 kg. Procedures: Famciclovir was administered orally or rectally in accordance with an incomplete crossover design. Three treatment groups, each comprising 4 elephants, received single doses of famciclovir (5 mg/kg, PO, or 5 or 15 mg/kg, rectally); there was a minimum 12-week washout period between subsequent famciclovir administrations. Serial blood samples were collected after each administration. Samples were analyzed for famciclovir and penciclovir with a validated liquid chromatography–mass spectroscopy assay. Results: Famciclovir was tolerated well for both routes of administration and underwent complete biotransformation to the active metabolite, penciclovir. Mean maximum plasma concentration of penciclovir was 1.3 μg/mL at 1.1 hours after oral administration of 5 mg/kg. Similar results were detected after rectal administration of 5 mg/kg. Mean maximum plasma concentration was 3.6 μg/mL at 0.66 hours after rectal administration of 15 mg/kg; this concentration was similar to results reported for humans receiving 7 mg/kg orally. Conclusions and Clinical Relevance: Juvenile Asian elephants are susceptible to elephant endotheliotropic herpesvirus. Although most infections are fatal, case reports indicate administration of famciclovir has been associated with survival of 3 elephants. In Asian elephants, a dose of 8 to 15 mg of famciclovir/kg given orally or rectally at least every 8 hours may result in penciclovir concentrations that are considered therapeutic in humans.

Objective: To develop and evaluate a rapid and accurate assay involving PCR amplification and electrospray ionization mass spectrometry of nucleic acid extracts from whole blood samples for the detection of Dirofilaria immitis infection in dogs. Sample: Whole blood nucleic acid extracts from 29 dogs experimentally infected with D immitis (and in which circulating D immitis antigen was detected) and 10 uninfected dogs. Procedures: 16 of the 29 whole blood samples from infected dogs were examined at the time of collection for circulating microfilaria. Nucleic acids were extracted from all whole blood specimens and underwent PCR amplification with 12 PCR primer pairs designed to detect a wide range of pathogens (including the Wolbachia endosymbiont of D immitis) and electrospray ionization mass spectrometry. Results: On the basis of assay results, heartworm infection was detected in 13 of 13 antigen-positive dogs of unknown microfilaria status, 11 of 11 antigen-positive dogs with circulating microfilaria, 0 of 3 antigen-positive dogs tested at 3 months after larval infection, 0 of 2 antigen-positive dogs with occult infections, and 0 of 10 uninfected dogs. Conclusions and Clinical Relevance: With the assay under investigation, it was possible to identify D immitis infection in dogs with circulating microfilaria via detection of the obligate Wolbachia endosymbiont of D immitis. It was not possible to identify dogs with occult infections, which suggested that circulating microfilaria must be present to detect infection with this assay, although further studies would be required to verify that finding.

Objective: To determine the pharmacokinetics of a long-acting formulation of ceftiofur, ceftiofur crystalline-free acid (CCFA), following SC injection to Asian elephants (Elephas maxim us). Animals: 11 adult Asian elephants. Procedures: Each elephant received CCFA (6.6 mg/kg, SC) in the area caudoventral to the base of an ear. Blood samples were collected from an ear vein immediately prior to and at 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after CCFA administration. Plasma concentrations of desfuroylceftiofur acetamide (the acetamide derivative of ceftiofur) were measured via ultrahigh-pressure liquid chromatography–tandem mass spectrometry. Data were analyzed via a noncompartmental pharmacokinetics approach. Results: The mean ± SD maximum plasma concentration of desfuroylceftiofur acetamide was 1.36 ± 0.74 μg/mL and was detected at 4718 ± 31.30 hours. The mean ± SD area under the curve from time 0 to infinity was 2278 ± 55.8 μg•h/mL, and the mean residence time from time 0 to infinity was 158.2 ± 90.2 hours. The terminal elimination half-life associated with the slope of the terminal phase had a harmonic mean ± pseudo-SD of 83.36 ± 30.01 hours. Conclusions and Clinical Relevance: Elephants tolerated CCFA at a dose of 6.6 mg/kg, SC, well. Dosing recommendations will depend on the mean inhibitory concentration of ceftiofur for each bacterial pathogen. Desfuroylceftiofur acetamide concentrations remained > 0.25 μg/mL for the entire 168-hour study period, which suggested CCFA would provide clinically relevant antimicrobial activity against certain pathogens for 7 to 10 days.

Objective: To determine whether the method of lipopolysaccharide (LPS) administration (intermittent vs continuous) affects the magnitude and duration of the systemic inflammatory response in horses and whether prolonged (48 hours) endotoxemia induces laminitis. Animals: 12 healthy adult horses (10 mares and 2 geldings). Procedures: Horses were randomly assigned to receive LPS (total dose, 80 μg; n = 4) or saline (0.9% NaCl) solution (80 mL/h; 4) via constant rate infusion or 8 bolus IV injections of LPS (10 μg, q 6 h;4) during a 48-hour period. Physical examinations were performed every 4 hours, inflammatory cytokine gene expression was determined for blood samples obtained every 8 hours, and IV glucose tolerance tests were performed. Results: All LPS-treated horses had signs of depression and mild colic; those signs abated as the study progressed. Administration of LPS increased expression of interleukin-1β, interleukin-6, and interleukin-8, but results were not significantly different between LPS treatment groups. Cytokine expression was significantly higher on the first day versus the second day of LPS treatment. Interleukin-1β expression was positively correlated with rectal temperature and expression of other cytokines. Glucose and insulin dynamics for both LPS groups combined did not differ significantly from those of the saline solution group. Signs of laminitis were not detected in any of the horses. Conclusions and Clinical Relevance: Horses developed LPS tolerance within approximately 24 hours after administration was started, and the method of LPS administration did not affect the magnitude or duration of systemic inflammation. Laminitis was not induced in horses.

Objective: To determine reference values for kaolin-activated thromboelastography in echocardiographically normal cats. Animals: 30 healthy cats without evidence of cardiomyopathy on echocardiographic examination. Procedures: All cats underwent echocardiographic examination, the findings of which were reviewed by a board-certified cardiologist. Cats that struggled (n = 10) received mild sedation with butorphanol and midazolam IM to permit phlebotomy without interruption in jugular venous blood flow. Blood samples were collected for analysis of thromboelastography variables, PCV, total solids concentration, platelet count, activated partial thromboplastin time, prothrombin time, fibrinogen concentration, and antithrombin concentration. Results: All 4 thromboelastography variables had < 5% mean intra-assay variability. Mean values were as follows: reaction time, 4.3 minutes; clotting time, 1.6 minutes; α angle, 66.5°; and maximum amplitude, 56.4 mm. Compared with nonsedated cats, cats that required sedation had a significantly shorter clotting time and greater α angle, whereas reaction time and maximum amplitude were not significantly different. Conclusions and Clinical Relevance: Kaolin-activated thromboelastography was a reliable test with unremarkable intra-assay variability in echocardiographically normal cats. Sedation may affect certain thromboelastography variables, but the effect is unlikely to be clinically important. It remains unknown whether subclinical cardiomyopathy has a significant effect on thromboelastography variables in cats.

Objective: To determine the ideal interval to image acquisition after IV injection of sodium fluoride F 18 (18F-NaF) and evaluate biodistribution of the radiopharmaceutical in clinically normal skeletally immature dogs. Animals: 4 female dogs. Procedures: Each dog was anesthetized for evaluation with a commercial hybrid positron emission tomography (PET)–CT instrument. A low–radiation dose, whole-body CT scan was acquired first. An IV injection of 18F-NaF (0.14 mCi/kg) was administered, and a dynamic PET scan centered over the heart and liver was acquired during a period of 120 minutes. Uptake of 18F-NaF in the blood pool, soft tissues, and skeletal structures was evaluated via region of interest analysis to derive standardized uptake values and time-activity curves, which were used to determine the optimal postinjection time for skeletal image acquisition. Biodistribution was also assessed from a final whole-body PET-CT scan acquired after the dynamic scan. Results: Time-activity curves revealed a rapid decrease in the amount of radiopharmaceutical in the blood pool and soft tissues and a rapid increase in the amount of radiopharmaceutical in bones soon after injection. At 50 minutes after injection, the greatest difference in uptake between soft tissues and bones was detected, with continued subtle increase in uptake in the bones. Uptake of 18F-NaF was slightly increased at growth plates and open ossification centers, compared with that at other parts of the bone. Conclusions and Clinical Relevance: At 50 minutes after IV injection of 18F-NaF at the dose evaluated, PET-CT yielded excellent bone-to-background ratio images for evaluation of the skeletal system in dogs.

Objective: To determine the pharmacokinetics of dexmedetomidine administered as a short-duration IV infusion in isoflurane-anesthetized cats. Animals: 6 healthy adult domestic female cats. Procedures: Dexmedetomidine hydrochloride was injected IV (10 μg/kg over 5 minutes [rate, 2 μg/kg/min]) in isoflurane-anesthetized cats. Blood samples were obtained immediately prior to and at 1, 2, 5, 6, 7, 10, 15, 30, 60, 90, 120, 240, and 480 minutes following the start of the IV infusion. Collected blood samples were transferred to tubes containing EDTA, immediately placed on ice, and then centrifuged at 3,901 × g for 10 minutes at 4°C. The plasma was harvested and stored at −20°C until analyzed. Plasma dexmedetomidine concentrations were determined by means of liquid chromatography–mass spectrometry. Dexmedetomidine plasma concentration-time data were fitted to compartmental models. Results: A 2-compartment model with input in and elimination from the central compartment best described the disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats. Weighted mean ± SEM apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state were 402 ± 47 mL/kg and 1,701 ± 200 mL/kg, respectively; clearance and terminal half-life (harmonic mean ± jackknife pseudo-SD) were 6.3 ± 2.8 mL/min/kg and 198 ± 75 minutes, respectively. The area under the plasma concentration curve and maximal plasma concentration were 1,061 ± 292 min•ng/mL and 17.6 ± 1.8 ng/mL, respectively. Conclusions and Clinical Relevance: Disposition of dexmedetomidine administered via short-duration IV infusion in isoflurane-anesthetized cats was characterized by a moderate clearance and a long terminal half-life.

Objective: To evaluate the effect of acepromazine maleate administered IV on platelet function assessed in healthy dogs by use of a modified thromboelastography assay. Animals: 6 healthy adult mixed-breed dogs. Procedures: Dogs received each of 3 treatments (saline [0.9% NaCl] solution [1 to 2 mL, IV] and acepromazine maleate [0.05 and 0.1 mg/kg, IV]) in a randomized crossover study with a minimum 3-day washout period between treatments. From each dog, blood samples were collected via jugular venipuncture immediately before and 30 and 240 minutes after administration of each treatment. A modified thromboelastography assay, consisting of citrated kaolin–activated (baseline assessment), reptilase-ADP–activated (ADP-activated), and reptilase-arachidonic acid (AA)–activated (AA-activated) thromboelastography, was performed for each sample. Platelet inhibition was evaluated by assessing the percentage change in maximum amplitude for ADP-activated or AA-activated samples, compared with baseline values. Percentage change in maximum amplitude was analyzed by use of Skillings-Mack tests with significance accepted at a family-wise error rate of P < 0.05 by use of Bonferroni corrections for multiple comparisons. Results: No significant differences were found in the percentage change of maximum amplitude from baseline for ADP-activated or AA-activated samples among treatments at any time. Conclusions and Clinical Relevance: Platelet function in dogs, as assessed by use of a modified thromboelastography assay, was not inhibited by acepromazine at doses of 0.05 or 0.1 mg/kg, IV. This was in contrast to previous reports in which it was suggested that acepromazine may alter platelet function via inhibition of ADP and AA.