Objective—To measure pharmacokinetics of levetiracetam (LEV) after single-dose oral administration in healthy dogs and determine whether pharmacokinetics changed after repeated oral dosing.
Animals—6 healthy adult dogs.
Procedures—Pharmacokinetics were calculated following administration of a single dose (mean, 21.7 mg/kg, PO; day 1) and after administration of the last dose following administration for 6 days (20.8 to 22.7 mg/kg, PO, q 8 h; days 2 to 7). Plasma LEV concentrations were determined by use of high-pressure liquid chromatography. Pharmacokinetic data were analyzed by use of a 1-compartment model with first-order absorption.
Results—Peak concentration occurred 0.6 hours after administration of the first dose, with an absorption half-life of 0.06 hours. Minimal accumulation occurred over the 7 days, with only a slight increase in total area under the concentration-versus-time curve from 268.52 ± 56.33 h·μg/mL (mean ± SD) to 289.31 ± 51.68 h·μg/mL after 7 days. Terminal half-life was 2.87 ± 0.21 hours after the first dose and 3.59 ± 0.82 hours after the last dose on day 7. Trough plasma concentrations were variable, depending on the time of day they were measured (morning trough concentration, 18.42 ± 5.16 μg/mL; midday trough concentration, 12.57 ± 4.34 μg/mL), suggesting a diurnal variation in drug excretion.
Conclusions and Clinical Relevance—Results indicated that the pharmacokinetics of LEV did not change appreciably after administration of multiple doses over 7 days. Administration of LEV at a dosage of 20 mg/kg, PO, every 8 hours to healthy dogs yielded plasma drug concentrations consistently within the therapeutic range established for LEV in humans.
Objective—To investigate the effect of topical application of undiluted lavender oil on sympathovagal activity in dogs.
Animals—5 healthy adult male Beagles.
Procedures—An ambulatory ECG monitor (Holter recorder) was placed on each dog (day0), and 48-hour ECGs were recorded, beginning at 8:00 the next day (day 1). Lavender oil (0.18 mL) or saline (0.9% NaCl) solution (0.18 mL) was topically applied to the inner pinnas of both ears of all dogs at 8:30, 12:00, 15:30, and 19:00 on day 2. Each trial was duplicated in each dog, with an interval of 3 to 4 days between trials. Spectral indices of heart rate variability, power in the high-frequency range, and the ratio of low-frequency to high-frequency power were calculated as an indirect estimate of autonomic nerve activity.
Results—When dogs were treated with lavender oil, the mean heart rate was significantly lower during the period of 19:00 to 22:30 on day 2, compared with the mean heart rate during the same period when dogs were treated with saline solution. On the other hand, high-frequency power during the period of 15:30 to 19:00 was significantly higher when dogs were treated with lavender oil, compared with the high-frequency power during the same period when dogs were treated with saline solution.
Conclusions and Clinical Relevance—The study revealed some evidence that topical application of lavender oil affected vagal activity in dogs. However, whether such an effect exists and whether lavender oil has a calming effect on dogs remains equivocal and requires additional investigation.
Objective—To measure the absolute and relative volumes of cranial vaults of Cavalier King Charles Spaniels (CKCSs) and other brachycephalic dogs for the purpose of evaluating a possible association between the volume of the caudal fossa (fossa caudalis cerebri; CF) and existence of Chiari-like malformation (CLM) and syringohydromyelia in CKCSs.
Animals—40 CKCSs and 25 brachycephalic dogs.
Procedures—The intracranial vault of all dogs was evaluated via computed tomography followed by magnetic resonance imaging. Volumes of the CF and the rostral and medial fossa (fossa rostralis et medialis cerebri) were determined. The ratio of the absolute volumes was calculated as the volume index (VI).
Results—All CKCSs had cranial characteristics consistent with CLM. There were no significant differences between CKCSs and brachycephalic dogs with respect to the VI and absolute volumes of the CF and rostral and medial fossas. The CKCSs without syringohydromyelia (n = 26) had a median VI of 0.1842, and CKCSs with syringohydromyelia (14) had a median VI of 0.1805. The median VI of other brachycephalic dogs was 0.1864. The VI did not differ among these 3 groups.
Conclusions and Clinical Relevance—Results of this study suggested that descent of the cerebellum into the foramen magnum and the presence of syringohydromyelia in CKCSs are not necessarily associated with a volume reduction in the CF of the skull.
Objective—To develop a clinically applicable technique for recording cord dorsum potentials (CDPs) following stimulation of the radial and ulnar nerves and establish reference values for radial and ulnar sensory nerve conduction velocities (SNCVs) in the wings of ducks.
Animals—8 clinically normal adult female mallard ducks (Anas platyrhynchos).
Procedures—Radial and ulnar compound nerve action potentials (CNAPs) and CDPs were recorded following distal sensory nerve stimulation. The CDPs were recorded from the interarcuate space between the last cervical vertebra and the first thoracic vertebra. Surgical dissection and transection of the brachial plexus in 1 anesthetized duck were performed to identify nerve root location and confirm functional loss of nerve conduction assessed by loss of the CDP.
Results—Radial and ulnar CNAPs and CDPs were consistently recorded in all birds. Median radial SNCV was 38.3 m/s (range, 36.0 to 49.0 m/s), and ulnar SNCV was 35.3 m/s (range, 28.0 to 40.0 m/s). Surgical transection of the brachial plexus resulted in complete loss of the CDP.
Conclusions and Clinical Relevance—Measurement of radial and ulnar SNCV or CDP is feasible in isoflurane-anesthetized mallard ducks. The CDP accurately reflects sensory nerve conduction through the brachial plexus. Assessment of brachial plexus function in mallard ducks via evaluations of SNCVs and CDPs may have application for diagnosis of traumatic injuries to the brachial plexus, evaluation of neuropathies associated with exposure to toxic chemicals, and assessment of the efficacy of interventions such as brachial plexus nerve blockade.
Objective—To evaluate the effect of intermittent oral administration of ponazuril on immunoconversion against Sarcocystis neurona in horses inoculated intragastrically with S neurona sporocysts.
Animals—20 healthy horses that were seronegative for S neurona–specific IgG.
Procedures—5 control horses were neither inoculated with sporocysts nor treated. Other horses (5 horses/group) each received 612,500 S neurona sporocysts via nasogastric tube (day 0) and were not treated or were administered ponazuril (20 mg/kg, PO) every 7 days (beginning on day 5) or every 14 days (beginning on day 12) for 12 weeks. Blood and CSF samples were collected on day – 1 and then every 14 days after challenge for western blot assessment of immunoconversion. Clinical signs of equine protozoal myeloencephalitis (EPM) were monitored, and tissues were examined histologically after euthanasia.
Results—Sera from all challenged horses yielded positive western blot results within 56 days. Immunoconversion in CSF was detected in only 2 of 5 horses that were treated weekly; all other challenged horses immunoconverted within 84 days. Weekly administration of ponazuril significantly reduced the antibody response against the S neurona 17-kd antigen in CSF. Neurologic signs consistent with EPM did not develop in any group; likewise, histologic examination of CNS tissue did not reveal protozoa or consistent degenerative or inflammatory changes.
Conclusions and Clinical Relevance—Administration of ponazuril every 7 days, but not every 14 days, significantly decreased intrathecal anti–S neurona antibody responses in horses inoculated with S neurona sporocysts. Protocols involving intermittent administration of ponazuril may have application in prevention of EPM.
Objective—To establish a method of F-wave evaluation and to determine normative values of F-wave parameters, including F-wave conduction velocity, persistence, and amplitude for the tibial nerve in cats.
Animals—30 clinically normal cats.
Procedures—F-waves elicited in the interosseous muscles by stimulation of the tibial nerve were recorded, and linear regression analyses of the shortest latency versus the length of the tibial nerve and the limb length were performed. F-wave persistence was calculated by dividing the number of recorded F-waves by the number of stimuli.
Results—The correlation coefficient between F-wave latency and nerve length was 0.92, and that between F-wave latency and limb length was 0.58. Mean ± SD F-wave conduction velocity of the tibial nerve was calculated to be 97.1 ± 5.0 m/s. Linear regression analysis yielded the regression equation as follows: F-wave latency (milliseconds) = 2.60 + (0.02 × nerve length [mm]). Mean F-wave persistence and amplitude were 98.7 ± 2.3% and 1.01 ± 0.62 mV, respectively.
Conclusions and Clinical Relevance—Results indicated that nerve length should be used for nerve conduction studies of F-waves in felids. The regression equation for F-wave latency, conduction velocity, persistence, and amplitude may contribute to the diagnosis of nervous system diseases or injury in cats, such as trauma to the spinal cord or diabetic neuropathy.
Objective—To compare radiographic morphology of the atlantoaxial region between Cavalier King Charles Spaniels (CKCSs) and dogs of other breeds and determine whether there was an association between radiographic morphology of the atlantoaxial region and syringomyelia in CKCSs.
Animals—65 CKCSs and 72 dogs of other breeds.
Procedures—The amount that the spinous process of the axis overlapped the dorsal arch of the atlas, the relative size of the spinous process of the axis, and the amount of widening of the atlantoaxial joint that occurred when the neck was moved from a neutral to a flexed position were measured on lateral radiographic projections of the atlantoaxial region. Magnetic resonance images were reviewed to identify CKCSs with syringomyelia.
Results—The amount of overlap of the atlas and axis and the relative size of the spinous process of the axis were significantly smaller in CKCSs than in dogs of other breeds. However, the amount of widening of the atlantoaxial joint that occurred when the neck was moved from a neutral to a flexed position was not significantly different between groups, and no association was detected between syringomyelia and excessive atlantoaxial joint space widening or between syringomyelia and an excessively small axial spinous process.
Conclusions and Clinical Relevance—Results suggested that radiographic morphology of the atlantoaxial region in CKCSs differs from morphology of that region in dogs of other breeds, but that these differences do not account for why some CKCSs develop syringomyelia and others do not.
Objective—To quantitatively evaluate expression of vascular endothelial growth factor (VEGF) in intracranial tumors in dogs and determine whether relationships exist between circulating and intratumoral VEGF concentrations and tumor type and grade.
Animals—27 dogs with primary intracranial neoplasms and 4 unaffected control dogs.
Procedures—Plasma and brain tumor samples were obtained from each dog, and plasma and intratumoral concentrations of VEGF were measured by use of an ELISA.
Results—Dogs with meningiomas (n = 11) were significantly older than dogs with oligodendrogliomas (7) or astrocytomas (9). Measurable VEGF was detected in all tumors, and a significant negative correlation between age and intratumoral VEGF concentration was detected. Age-adjusted comparisons identified significant differences in intratumoral VEGF concentrations among all tumor types; the highest VEGF concentrations were associated with astrocytomas. Within each tumor type, increasing tumor grade was significantly associated with increasing VEGF expression. Plasma VEGF concentrations were detectable in 9 of 27 dogs; the proportion of dogs with astrocytomas and a detectable circulating VEGF concentration (7/9 dogs) was significantly higher than the proportion of dogs with meningiomas (1/11 dogs) or oligodendrogliomas (1/7 dogs) with a detectable circulating VEGF concentration.
Conclusions and Clinical Relevance—Overexpression of VEGF appears common in canine astrocytomas, oligodendrogliomas, and meningiomas. In the neoplasms examined, intratumoral VEGF concentrations correlated well with tumor malignancy. The VEGF expression patterns paralleled those of analogous human tumors, providing evidence that dogs are a suitable species in which to study angiogenesis and intracranial neoplasia for human application.
Objective—To determine whether antiepileptic drugs (AEDs) are substrates for canine P-glycoprotein (P-gp).
Sample Population—OS2.4/Doxo cells (canine osteosarcoma cells induced via exposure to doxorubicin to highly express P-gp).
Procedures—Competitive inhibition of rhodamine 123 efflux from OS2.4/Doxo cells was used to determine whether AEDs were substrates for canine P-gp. Flow cytometry was used to quantify mean fluorescence intensity of cells treated with rhodamine alone and in combination with each experimental drug.
Results—Known P-gp substrate drugs ivermectin and cyclosporin A altered rhodamine efflux by 90% and 95%, respectively. Experimental drugs altered rhodamine efflux weakly (diazepam, gabapentin, lamotrigine, levetiracetam, and phenobarbital) or not at all (carbamazepine, felbamate, phenytoin, topirimate, and zonisamide).
Conclusions and Clinical Relevance—At clinically relevant doses, it appeared that AEDs were weak substrates (diazepam, gabapentin, lamotrigine, levetiracetam, and phenobarbital) or were not substrates (carbamazepine, felbamate, phenytoin, topirimate, and zonisamide) for canine P-gp. Therefore, it seems unlikely that efficacy of these AEDs is affected by P-gp expression at the blood-brain barrier in dogs.
Objective—To evaluate cell surface markers of bone marrow–derived canine mesenchymal stem cells (MSCs) by use of flow cytometric analysis and determine whether canine MSCs express proteins specific to neuronal and glial cells.
Sample Population—Bone marrow aspirates collected from iliac crests of 5 cadavers of young adult dogs.
Procedures—Flow cytometric analysis was performed to evaluate cell surface markers and homogeneity of third-passage MSCs. Neural differentiation of canine MSCs was induced by use of dibutyryl cAMP and methyl-isobutylxanthine. Expressions of neuronal (β III-tubulin) and glial (glial fibrillary acidic protein [GFAP] and myelin basic protein) proteins were evaluated by use of immunocytochemical and western blot analyses before and after neural differentiation.
Results—Third-passage canine MSCs appeared morphologically homogeneous and shared phenotypic characteristics with human and rodent MSCs. Immunocytochemical and western blot analyses revealed that canine MSCs constitutively expressed β III-tubulin and GFAP. After induction of neural differentiation, increased expression of GFAP was found in all samples, whereas such change was inconsistent in β III-tubulin expression. Myelin basic protein remained undetectable on canine MSCs for these culture conditions.
Conclusions and Clinical Relevance—Canine bone marrow–derived mononuclear cells yielded an apparently homogeneous population of MSCs after expansion in culture. Expanded canine MSCs constitutively expressed neuron or astrocyte specific proteins. Furthermore, increases of intracellular cAMP concentrations induced increased expression of GFAP on canine MSCs, which suggests that these cells may have the capacity to respond to external signals. Canine MSCs may hold therapeutic potential for treatment of dogs with neurologic disorders.