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 evaluate the pharmacokinetics of hydrocodone (delivered in combination with acetaminophen) and tramadol in dogs undergoing tibial plateau leveling osteotomy (TPLO). ANIMALS 50 client-owned dogs. PROCEDURES Dogs were randomly assigned to receive tramadol hydrochloride (5 to 7 mg/kg, PO, q 8 h; tramadol group) or hydrocodone bitartrate–acetaminophen (0.5 to 0.6 mg of hydrocodone/kg, PO, q 8 h; hydrocodone group) following TPLO with standard anesthetic and surgical protocols. Blood samples were collected for pharmacokinetic analysis of study drugs and their metabolites over an 8-hour period beginning after the second dose of the study medication. RESULTS The terminal half-life, maximum serum concentration, and time to maximum serum concentration for tramadol following naïve pooled modeling were 1.56 hours, 155.6 ng/mL, and 3.90 hours, respectively. Serum concentrations of the tramadol metabolite O-desmethyltramadol (M1) were low. For hydrocodone, maximum serum concentration determined by naïve pooled modeling was 7.90 ng/mL, and time to maximum serum concentration was 3.47 hours. The terminal half-life for hydrocodone was 15.85 hours, but was likely influenced by delayed drug absorption in some dogs and may not have been a robust estimate. Serum concentrations of hydromorphone were low. CONCLUSIONS AND CLINICAL RELEVANCE The pharmacokinetics of tramadol and metabolites were similar to those in previous studies. Serum tramadol concentrations varied widely, and concentrations of the active M1 metabolite were low. Metabolism of hydrocodone to hydromorphone in dogs was poor. Further study is warranted to assess variables that affect metabolism and efficacy of these drugs in dogs.

Objective—To describe findings of 3.0-T multivoxel proton magnetic resonance spectroscopy (1H-MRS) in dogs with inflammatory and neoplastic intracranial disease and to determine the applicability of 1H-MRS for differentiating between inflammatory and neoplastic lesions and between meningiomas and gliomas. Animals—33 dogs with intracranial disease (19 neoplastic [10 meningioma, 7 glioma, and 2 other] and 14 inflammatory). Procedures—3.0-T multivoxel 1H-MRS was performed on neoplastic or inflammatory intracranial lesions identified with conventional MRI. N-acetylaspartate (NAA), choline, and creatine concentrations were obtained retrospectively, and metabolite ratios were calculated. Values were compared for metabolites separately, between lesion categories (neoplastic or inflammatory), and between neoplastic lesion types (meningioma or glioma) by means of discriminant analysis and 1-way ANOVA. Results—The NAA-to-choline ratio was 82.7% (62/75) accurate for differentiating neoplastic from inflammatory intracranial lesions. Adding the NAA-to-creatine ratio or choline-to-creatine ratio did not affect the accuracy of differentiation. Neoplastic lesions had lower NAA concentrations and higher choline concentrations than inflammatory lesions, resulting in a lower NAA-to-choline ratio, lower NAA-to-creatine ratio, and higher choline-to-creatine ratio for neoplasia relative to inflammation. No significant metabolite differences between meningiomas and gliomas were detected. Conclusions and Clinical Relevance—1H-MRS was effective for differentiating inflammatory lesions from neoplastic lesions. Metabolite alterations for 1H-MRS in neoplasia and inflammation in dogs were similar to changes described for humans. Use of 1H-MRS provided no additional information for differentiating between meningiomas and gliomas. Proton MRS may be a beneficial adjunct to conventional MRI in patients with high clinical suspicion of inflammatory or neoplastic intracranial lesions.

Objective—To determine relative concentrations of selected major brain tissue metabolites and their ratios and lobar variations by use of 3-T proton (hydrogen 1 [1H]) magnetic resonance spectroscopy (MRS) of the brain of healthy dogs. Animals—10 healthy Beagles. Procedures—3-T 1H MRS at echo times of 144 and 35 milliseconds was performed on 5 transverse slices and 1 sagittal slice of representative brain lobe regions. Intravoxel parenchyma was classified as white matter, gray matter, or mixed (gray and white) and analyzed for relative concentrations (in arbitrary units) of N-acetylaspartate (NAA), choline, and creatine (ie, height at position of peak on MRS graph) as well as their ratios (NAA-to-choline, NAA-to-creatine, and choline-to-creatine ratios). Peak heights for metabolites were compared between echo times. Peak heights for metabolites and their ratios were correlated and evaluated among matter types. Yield was calculated as interpretable voxels divided by available lobar voxels. Results—Reference ranges of the metabolite concentration ratios were determined at an echo time of 35 milliseconds (NAA-to-choline ratio, 1.055 to 2.224; NAA-to-creatine ratio, 1.103 to 2.161; choline-to-creatine ratio, 0.759 to 1.332) and 144 milliseconds (NAA-to-choline ratio, 0.687 to 1.788; NAA-to-creatine ratio, 0.984 to 2.044; choline-to-creatine ratio, 0.828 to 1.853). Metabolite concentration ratios were greater in white matter than in gray matter. Voxel yields ranged from 43% for the temporal lobe to 100% for the thalamus. Conclusions and Clinical Relevance—Metabolite concentrations and concentration ratios determined with 3-T 1H MRS were not identical to those in humans and were determined for clinical and research investigations of canine brain disease.

Objective—To evaluate markers of in vivo platelet function (urinary 11-dehydro-thromboxane B2 [11-dehydroTXB2] and 2,3-dinorTXB2) and assess their response to administration of 2 commonly used dosages of aspirin in healthy dogs. Animals—20 healthy dogs. Procedures—Urine was collected prior to aspirin administration and on the morning following the last evening administration. Twenty dogs received aspirin (1 mg/kg, PO, q 24 h) for 7 consecutive doses. After a washout period of 5 months, 10 dogs received a single dose of aspirin (10 mg/kg, PO). Concentrations of urinary thromboxane metabolites 11-dehydroTXB2 and 2,3-dinorTXB2 were measured via ELISA, and values were normalized to urine creatinine concentration. Results—Median baseline 11-dehydroTXB2 concentrations were 0.38 ng/mg of creatinine (range, 0.15 to 1.13 ng/mg). Mean ± SD baseline 2 at a 3-dinorTXB2 concentrations were 6.75 ± 2.77 ng/mg of creatinine. Administration of aspirin at a dosage of 1 mg/kg, PO, every 24 hours for 7 days did not significantly decrease urinary 11-dehydroTXB2 concentration, but administration of the single aspirin dose of 10 mg/kg did significantly decrease 11-dehydroTXB2 concentration by a median of 45.5% (range, 28.2% to 671%). Administration of the 1 mg/kg aspirin dosage significantly decreased urinary 2,3-dinorTXB2 concentration by a mean ± SD of 33.0 ± 23.7%. Administration of the single aspirin dose of 10 mg/kg also significantly decreased 2,3-dinorTXB2 concentration by a mean ± SD of 46.7 ± 12.6%. Conclusions and Clinical Relevance—Aspirin administration (1 mg/kg/d) may be insufficient for reliable platelet inhibition in healthy dogs.

Objective—To evaluate the elimination pharmacokinetics of a single IM injection of a long-acting ceftiofur preparation (ceftiofur crystalline-free acid [CCFA]) in healthy adult helmeted guineafowl (Numida meleagris). Animals—14 healthy adult guineafowl. Procedures—1 dose of CCFA (10 mg/kg) was administered IM to each of the guineafowl. Blood samples were collected intermittently via jugular venipuncture over a 144-hour period. Concentrations of ceftiofur and all desfuroylceftiofur metabolites were measured in plasma via high-performance liquid chromatography. Results—No adverse effects of drug administration or blood collection were observed in any bird. The minimal inhibitory concentration (MIC) for many bacterial pathogens of poultry and domestic ducks (1 μg/mL) was achieved by 1 hour after administration in most birds and by 2 hours in all birds. A maximum plasma concentration of 5.26 μg/mL was reached 19.3 hours after administration. Plasma concentrations remained higher than the MIC for at least 56 hours in all birds and for at least 72 hours in all but 2 birds. The harmonic mean ± pseudo-SD terminal half-life of ceftiofur was 29.0 ± 4.93 hours. The mean area under the curve was 306 ± 69.3 μg•h/mL, with a mean residence time of 52.0 ± 8.43 hours. Conclusions and Clinical Relevance—A dosage of 10 mg of CCFA/kg, IM, every 72 hours in helmeted guineafowl should provide a sufficient plasma drug concentration to inhibit growth of bacteria with an MIC ≤ 1 μg/mL. Clinical use should ideally be based on bacterial culture and antimicrobial susceptibility data and awareness that use of CCFA in avian patients constitutes extralabel use of this product.

The cause of species difference in the susceptibility of erythrocytes to L-sorbose, and the difference in the hemolytic effect of sorbose on high potassium-containing (HK) and low potassium-containing (LK) canine erythrocytes were examined. L-sorbose was phosphorylated in canine erythrocytes, but not in human erythrocytes. Furthermore, sorbose-1-phosphate, a metabolite of L-sorbose, strongly inhibited the hexokinase of LK canine erythrocytes, but not that of HK canine erythrocytes. These results strongly indicated that inhibition of hexokinase by sorbose-1-phosphate in LK erythrocytes induced severe glycolytic limitation in these cells, resulting in hemolysis, and that HK erythrocytes are resistant to sorbose-induced hemolysis because these cells have a high hexokinase activity.

The lipoxygenase metabolites of arachidonic acid have an important role in lymphocyte activation. We used a specific 5-lipoxygenase inhibitor, A-63162, to examine the role of 5-lipoxygenase (5-LO) in equine blood mononuclear cell (BMC) proliferation and leukotriene B4 (LTB4) synthesis after stimulation with mitogen (phytohemagglutinin, PHA) or calcium ionophore (A23187). The A-63162 inhibited PHA-induced equine BMC proliferation and, at the same concentration, also inhibited A23187-induced LTB4 synthesis. The presence of exogenous interleukin 2 (IL-2) or the cyclooxygenase inhibitor indomethacin, failed to reverse the immunosuppression caused by A-63162. Further, we found that A-63162, at the concentration that inhibited BMC proliferation and LTB4 synthesis, had no effect on BMC viability. The addition of the specific protein kinase C inhibitor, H-7, did not inhibit A23187-induced LTB4 synthesis. Results indicate that 5-lipoxygenase metabolites may have an important role in equine lymphocyte activation and that protein kinase C has no role in regulating LTB4 production after A23187 stimulation.

Plasma disposition and urinary recovery of sulfamethazine (SMZ), its N4-acetylated metabolite (N4AcSMZ), and 2 of its hydroxylated metabolites--5-hydroxysulfamethazine 5OHSMZ) and 6-hydroxymethylsulfamethazine (6CH2OHSMZ)--were determined in either sex of 4 animal species: rats, dwarf goats, rabbits, and cattle. Rats, rabbits, and dwarf goats had significant (P < 0.01) sex difference in SMZ plasma clearance. Male rats had higher plasma clearance than did female rats, and excreted higher amounts of the hydroxy metabolites and lower amounts of N4AcSMZ. The N4AcSMZ metabolite was predominant in plasma and urine of rabbits. Male rabbits had higher plasma clearance than did female rabbits, but differences in metabolite profile were not apparent. With regard to plasma SMZ elimination, the situation in goats was opposite to that in rats. Male goats had considerably lower clearance than did female goats. This was associated with a lower hydroxylation rate in males. Plasma half-life of SMZ in cows was lower than that in bulls, probably because of a smaller distribution volume in cows. Compared with elimination via urine, elimination via milk was negligible in cows. Significant differences in metabolite profiles were not found between bulls and cows. Similar to those in rats and mice, hormone-dependent xenobiotic metabolic pathways may exist in other species. Depending on species and xenobiotic compound residue concentrations of xenobiotics, their metabolites, or both may differ with sex of the animal, or may be altered after treatment with anabolic hormones.

The toxicity of zinc ethylene-bis-dithiocarbamate (zineb), a widely used fungicide, was studied in four 4-week-old Friesian calves with immature rumen function. Calves were first subjected to liver biopsy, and thereafter, 3 of them were orally administered 200 mg of zineb/kg of body weight daily for 80 days, whereas the fourth calf served as control and remained untreated. Clinical, hematologic, and pathologic (including ultrastructural) findings were recorded. The distribution in body fluids and tissues of the parent compound and one of its main metabolites, ethylenethiourea (ETU), also was examined. Treated calves had unthrifty appearance and reduction in weight gain. They also had remarkable impairment of thyroid function, as reflected by reduction in serum concentrations of triiodothyronine and thyroxine and increase in weight of the thyroid gland associated with epithelial vacuolization and foci of hyperplasia. Moderate increase in liver glycogen content and impairment in maturation of germ cells were recorded consistently. Whereas zineb was widely distributed in body tissues, ETU accumulated mainly in the liver and the thyroid gland, although noticeable concentrations also were attained in muscle. Data were consistent with involvement of ETU mainly in the pathogenesis of thyroid gland lesions, and indicate that unweaned calves given zineb develop a clinicopathologic syndrome that does not differ qualitatively from that already described in adult cattle exposed to zineb.