OBJECTIVES To determine, following oral administration of famciclovir, pharmacokinetic (PK) parameters for 2 of its metabolites (penciclovir and BRL42359) in plasma and tears of healthy cats so that famciclovir dosage recommendations for the treatment of herpetic disease can be optimized. ANIMALS 7 male domestic shorthair cats. PROCEDURES In a crossover study, each of 3 doses of famciclovir (30, 40, or 90 mg/kg) was administered every 8 or 12 hours for 3 days. Six cats were randomly assigned to each dosage regimen. Plasma and tear samples were obtained at predetermined times after famciclovir administration. Pharmacokinetic parameters were determined for BRL42359 and penciclovir by compartmental and noncompartmental methods. Pharmacokinetic-pharmacodynamic (PK-PD) indices were determined for penciclovir and compared among all dosage regimens. RESULTS Compared with penciclovir concentrations, BRL42359 concentrations were 5- to 11-fold greater in plasma and 4- to 7-fold greater in tears. Pharmacokinetic parameters and PK-PD indices for the 90 mg/kg regimens were superior to those for the 30 and 40 mg/kg regimens, regardless of dosing frequency. Penciclovir concentrations in tears ranged from 18% to 25% of those in plasma. Administration of 30 or 40 mg/kg every 8 hours achieved penciclovir concentrations likely to be therapeutic in plasma but not in tears. Penciclovir concentrations likely to be therapeutic in tears were achieved only with the two 90 mg/kg regimens. CONCLUSIONS AND CLINICAL RELEVANCE In cats, famciclovir absorption is variable and its metabolism saturable. Conversion of BRL42359 to penciclovir is rate limiting. The recommended dosage of famciclovir is 90 mg/kg every 12 hours for cats infected with feline herpesvirus.

OBJECTIVE To determine pharmacodynamic and pharmacokinetic profiles of aminocaproic acid (ACA) by use of a thromboelastography (TEG)-based in vitro model of hyperfibrinolysis and high-performance liquid chromatography–mass spectrometry. ANIMALS 5 healthy adult dogs. PROCEDURES A single dose of injectable ACA (20, 50, or 100 mg/kg) or an ACA tablet (approximately 100 mg/kg) was administered orally. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, and 240 minutes after ACA administration for pharmacokinetic analysis. Samples were obtained at 0, 60, and 240 minutes for pharmacodynamic analysis by use of a TEG model of hyperfibrinolysis. RESULTS No adverse effects were detected. In the hyperfibrinolysis model, after all doses, a significantly higher TEG maximum amplitude (clot strength), compared with baseline, was detected at 60 and 240 minutes. Additionally, the percentage of fibrinolysis was reduced from the baseline value at 60 and 240 minutes, with the greatest reduction at 60 minutes. At 240 minutes, there was significantly less fibrinolysis for the 100 mg/kg dose than the 20 mg/kg dose. Maximum plasma ACA concentration was dose dependent. There was no significant difference in pharmacokinetic parameters between 100 mg/kg formulations. CONCLUSIONS AND CLINICAL RELEVANCE In an in vitro model of hyperfibrinolysis, ACA inhibited fibrinolysis at all doses tested. At 240 minutes after administration, the 100 mg/kg dose inhibited fibrinolysis more effectively than did the 20 mg/kg dose. Thus, ACA may be useful for in vivo prevention of fibrinolysis in dogs. IMPACT FOR HUMAN MEDICINE These data may improve research models of hyperfibrinolytic diseases.

OBJECTIVE To evaluate use of single manual alveolar recruitment maneuvers (ARMs) to eliminate atelectasis during CT of anesthetized foals. ANIMALS 6 neonatal Standardbred foals. PROCEDURES Thoracic CT was performed on spontaneously breathing anesthetized foals positioned in sternal (n = 3) or dorsal (3) recumbency when foals were 24 to 36 hours old (time 1), 4 days old (time 2), 7 days old (time 3), and 10 days old (time 4). The CT images were collected without ARMs (all times) and during ARMs with an internal airway pressure of 10, 20, and 30 cm H2O (times 2 and 3). Quantitative analysis of CT images measured whole lung and regional changes in attenuation or volume with ARMs. RESULTS Increased attenuation and an alveolar pattern were most prominent in the dependent portion of the lungs. Subjectively, ARMs did not eliminate atelectasis; however, they did incrementally reduce attenuation, particularly in the nondependent portion of the lungs. Quantitative differences in lung attenuation attributable to position of foal were not identified. Lung attenuation decreased significantly (times 2 and 3) and lung volume increased significantly (times 2 and 3) after ARMs. Changes in attenuation and volume were most pronounced in the nondependent portion of the lungs and at ARMs of 20 and 30 cm H2O. CONCLUSIONS AND CLINICAL RELEVANCE Manual ARMs did not eliminate atelectasis but reduced attenuation in nondependent portions of the lungs. Positioning of foals in dorsal recumbency for CT may be appropriate when pathological changes in the ventral portion of the lungs are suspected.

OBJECTIVE To evaluate safety and toxicokinetic profiles associated with daily oral administration of grapiprant, a new analgesic that selectively blocks the prostaglandin E2 EP4 receptor, to cats. ANIMALS 24 healthy domestic shorthair cats (12 males and 12 females). PROCEDURES Cats were randomly assigned (3 of each sex/group) to receive a placebo capsule or grapiprant at 3, 9, or 15 mg/kg, administered PO once daily for 28 days, beginning on day 0. Food consumption and behavior were observed daily, body weight was measured weekly, and clinicopathologic tests were performed on blood and urine samples collected on days −7, 14, and 25. Blood samples for toxicokinetic analyses were collected after treatment on days 0 and 27. Cats were euthanized on day 28, and full necropsies and histologic evaluations were performed. RESULTS Grapiprant rapidly reached peak serum concentrations and maintained substantial concentrations throughout the 28-day period. By day 27, maximum serum concentrations ranged from 683 ng/mL to 4,950 ng/mL, which were attained by 1 to 4 hours after administration. Serum half-lives on day 27 ranged from approximately 2 to 14 hours (median, approx 5 to 6 hours). Grapiprant was well tolerated, and no adverse effects were detected at doses ≤ 15 mg/kg. No significant effects of grapiprant were identified on body weight, food consumption, clinicopathologic variables, or gross or histologic necropsy findings. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested the safety of daily oral administration of grapiprant to cats. Additional studies are needed to evaluate the efficacy of grapiprant for treatment of cats with osteoarthritis.

OBJECTIVE To compare the anticollagenase efficacy of fresh feline, canine, and equine serum and plasma on in vitro corneal degradation. SAMPLE Grossly normal corneas from recently euthanized dogs, cats, and horses and fresh serum and plasma from healthy dogs, cats, and horses. PROCEDURES Serum and plasma were pooled by species and used for in vitro experiments. Corneas were collected and stored at −80°C. Sections of cornea were dried, weighed, and incubated in saline (0.9% NaCl) solution with clostridial collagenase and homologous fresh serum or plasma. Corneal degradation was assessed as the percentage of corneal weight loss and hydroxyproline concentration, compared with results for positive and negative control samples. RESULTS Homologous fresh serum and plasma significantly reduced the percentage of corneal weight loss, compared with results for positive control samples. No significant difference was found in percentage of corneal weight loss between incubation with serum or plasma for feline, canine, and equine corneas. Canine serum and plasma significantly reduced hydroxyproline concentrations, whereas inclusion of feline and equine serum or plasma did not, compared with results for positive control samples. Hydroxyproline concentrations were moderately correlated with percentage of corneal weight loss for feline samples and weakly correlated for equine samples, but they were not correlated for canine samples. CONCLUSIONS AND CLINICAL RELEVANCE In this study, the anticollagenase efficacy of fresh feline, canine, and equine serum was not different from that of plasma. Plasma should be an acceptable substitute for serum in the topical treatment of keratomalacia.

OBJECTIVE To characterize the elution of platinum from carboplatin-impregnated calcium sulfate hemihydrate (CSH) beads in vitro. SAMPLE 60 carboplatin-impregnated CSH beads and 9 CSH beads without added carboplatin (controls). PROCEDURES Carboplatin-impregnated CSH beads (each containing 4.6 mg of carboplatin [2.4 mg of platinum]) were placed into separate 10-mL plastic tubes containing 5 mL of PBSS in groups of 1, 3, 6, or 10; 3 control beads were placed into a single tube of PBSS at the same volume. Experiments were conducted in triplicate at 37°C and a pH of 7.4 with constant agitation. Eluent samples were collected at 1, 2, 3, 6, 12, 24, and 72 hours. Samples were analyzed for platinum content by inductively coupled plasma–mass spectrometry. RESULTS The mean concentration of platinum released per carboplatin-impregnated bead over 72 hours was 445.3 mg/L. Cumulative concentrations of platinum eluted increased as the number of beads per tube increased. There was a significant difference in platinum concentrations over time, with values increasing over the first 12 hours and then declining for all tubes. There was also a significant difference in percentage of total incorporated platinum released into tubes with different numbers of beads: the percentage of eluted platinum was higher in tubes containing 1 or 3 beads than in those containing 6 or 10 beads. CONCLUSIONS AND CLINICAL RELEVANCE Carboplatin-impregnated CSH beads eluted platinum over 72 hours. Further studies are needed to determine whether implantation of carboplatin-impregnated CSH beads results in detectable levels of platinum systemically and whether the platinum concentrations eluted locally are toxic to tumor cells.

OBJECTIVE To evaluate effects of simultaneous intra-articular and IV injection of autologous adipose-derived stromal vascular fraction (SVF) and platelet-rich plasma (PRP) to dogs with osteoarthritis of the hip joints. ANIMALS 22 client-owned dogs (12 placebo-treated [control] dogs and 10 treated dogs). PROCEDURES Dogs with osteoarthritis of the hip joints that caused signs of lameness or discomfort were characterized on the basis of results of orthopedic examination, goniometry, lameness score, the Canine Brief Pain Inventory (CBPI), a visual analogue scale, and results obtained by use of a pressure-sensing walkway at week 0 (baseline). Dogs received a simultaneous intraarticular and IV injection of SVF and PRP or a placebo. Dogs were examined again 4, 8, 12, and 24 weeks after injection. RESULTS CBPI scores were significantly lower for the treatment group at week 24, compared with scores for the control group. Mean visual analogue scale score for the treatment group was significantly higher at week 0 than at weeks 4, 8, or 24. Dogs with baseline peak vertical force (PVF) in the lowest 25th percentile were compared, and the treatment group had a significantly higher PVF than did the control group. After the SVF-PRP injection, fewer dogs in the treated group than in the control group had lameness confirmed during examination. CONCLUSIONS AND CLINICAL RELEVANCE For dogs with osteoarthritis of the hip joints treated with SVF and PRP, improvements in CBPI and PVF were evident at some time points, compared with results for the control group.

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 investigate metabolite concentrations of the brains of dogs with intracranial neoplasia or noninfectious meningoencephalitis by use of short echo time, single voxel proton magnetic resonance spectroscopy (1H MRS) at 3.0 T. ANIMALS 29 dogs with intracranial lesions (14 with neoplasia [3 oligodendromas, 3 glioblastomas multiformes, 3 astrocytomas, 2 lymphomas, and 3 meningiomas] and 15 is with noninfectious meningoencephalitis) and 10 healthy control dogs. PROCEDURES Short echo time, single voxel 1H-MRS at 3.0 T was performed on neoplastic and noninfectious inflammatory intracranial lesions identified with conventional MRI. Metabolites of interest included N-acetyl aspartate (NAA), total choline, creatine, myoinositol, the glutamine-glutamate complex (Glx), glutathione, taurine, lactate, and lipids. Data were analyzed with postprocessing fitting algorithm software. Metabolite concentrations relative to brain water content were calculated and compared with results for the healthy control dogs, which had been previously evaluated with the same 1H MRS technique. RESULTS NAA, creatine, and Glx concentrations were reduced in the brains of dogs with neoplasia and noninfectious meningoencephalitis, whereas choline concentration was increased. Concentrations of these metabolites differed significantly between dogs with neoplasia and dogs with noninfectious meningoencephalitis. Concentrations of NAA, creatine, and Glx were significantly lower in dogs with neoplasia, whereas the concentration of choline was significantly higher in dogs with neoplasia. Lipids were predominantly found in dogs with high-grade intra-axial neoplasia, meningioma, and necrotizing meningoencephalitis. A high concentration of taurine was found in 10 of 15 dogs with noninfectious meningoencephalitis. CONCLUSIONS AND CLINICAL RELEVANCE 1H MRS provided additional metabolic information about intracranial neoplasia and noninfectious meningoencephalitis in dogs.

OBJECTIVE To compare clinical disease and lung lesions in calves experimentally inoculated with Histophilus somni 5 days after metaphylactic administration of tildipirosin or tulathromycin. ANIMALS Twenty-four 3-month-old Holstein and Holstein-crossbreed steers. PROCEDURES Calves were randomly allocated to 3 groups of 8 calves. On day 0, calves in group 1 received tildipirosin (4 mg/kg, SC), calves in group 2 received tulathromycin (2.5 mg/kg, SC), and calves in group 3 received isotonic saline (0.9% NaCl) solution (1 mL/45 kg, SC; control). On day 5, calves were inoculated with 10 mL of a solution containing H somni strain 7735 (1.6 × 109 CFUs/mL, intrabronchially; challenge). Calves were clinically evaluated on days 5 through 8 and euthanized on day 8. The lungs were grossly evaluated for evidence of pneumonia, and bronchial secretion samples underwent bacteriologic culture. RESULTS The mean clinical score for each group was significantly increased 12 hours after challenge, compared with that immediately before challenge, and was significantly lower for tildipirosin-treated calves on days 6, 7, and 8, compared with those for tulathromycin-treated and control calves. The mean percentage of lung consolidation for tildipirosin-treated calves was significantly lower than those for tulathromycin-treated and control calves. Histophilus somni was isolated from the bronchial secretions of some tulathromycin-treated and control calves but was not isolated from tildipirosin-treated calves. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that metaphylactic administration of tildipirosin to calves 5 days prior to H somni challenge prevented subsequent culture of the pathogen from bronchial secretions and was more effective in minimizing clinical disease and lung lesions than was metaphylactic administration of tulathromycin.