To compare pharmacokinetics of levetiracetam in serum and CSF of cats after oral administration of extended-release (ER) levetiracetam.
9 healthy cats.
Cats received 1 dose of a commercially available ER levetiracetam product (500 mg, PO). Thirteen blood and 10 CSF samples were collected over a 24-hour period for pharmacokinetic analysis. After 1 week, cats received 1 dose of a compounded ER levetiracetam formulation (500 mg, PO), and samples were obtained at the same times for analysis.
CSF concentrations of levetiracetam closely paralleled serum concentrations. There were significant differences between the commercially available product and the compounded formulation for mean ± SD serum maximum concentration (Cmax; 126 ± 33 μg/mL and 169 ± 51 μg/mL, respectively), Cmax corrected for dose (0.83 ± 0.10 μg/mL/mg and 1.10 ± 0.28 μg/mL/mg, respectively), and time to Cmax (5.1 ± 1.6 hours and 3.1 ± 1.5 hours, respectively). Half-life for the commercially available product and compounded formulation of ER levetiracetam was 4.3 ± 2.0 hours and 5.0 ± 1.6 hours, respectively.
CONCLUSIONS AND CLINICAL RELEVANCE
The commercially available product and compounded formulation of ER levetiracetam both maintained concentrations in healthy cats 12 hours after oral administration that have been found to be therapeutic in humans (ie, 5 μg/mL). Results of this study supported dosing intervals of 12 hours, and potentially 24 hours, for oral administration of ER levetiracetam to cats. Monitoring of serum concentrations of levetiracetam can be used as an accurate representation of levetiracetam concentrations in CSF of cats.
To evaluate safety of stylet-in and stylet-out techniques for collection of CSF from the cisterna magna and to assess whether there were differences between techniques with regard to contamination of samples, sample quality, and efficiency of collection.
10 adult purpose-bred research Beagles.
A prospective crossover study was conducted. Preanesthetic physical and neurologic examinations and hematologic analyses were performed. Dogs were anesthetized, and collection of CSF samples from the cisterna magna by use of a stylet-in or stylet-out technique was performed. Two weeks later, samples were collected with the other sample collection technique. Samples of CSF were processed within 1 hour after collection.
Cellular debris was detected in higher numbers in stylet-in samples, although this did not affect sample quality. The stylet-out technique was performed more rapidly. No adverse effects were detected for either technique.
CONCLUSIONS AND CLINICAL RELEVANCE
Both techniques could be safely performed in healthy anesthetized dogs. The stylet-out technique was performed more rapidly and yielded a sample with less cellular debris. Both techniques can be used in clinical practice to yield CSF samples with good diagnostic quality.
OBJECTIVE To retrospectively evaluate the epidemiological and morphological features and outcome of surgical treatment of incomplete ossification of the dorsal neural arch of the atlas (IODA) in dogs with atlantoaxial instability (AAI).
ANIMALS 106 AAI-affected dogs that underwent ventral fixation of the atlantoaxial joint.
PROCEDURES Medical records and CT images for each dog were reviewed. Dogs were allocated to 1 of 2 groups on the basis of the presence or absence of IODA or of dens abnormalities (DAs) in CT images.
RESULTS Of the 106 dogs with AAI, 75 had and 31 did not have IODA; 70 had and 36 did not have DAs. Incomplete ossification was present in the cranialmost, central, or caudalmost portion of the dorsal neural arch of the atlas in 59, 39, and 28 dogs, respectively; 2 or 3 portions were affected in 29 and 11 dogs, respectively. The mean CT value (in Hounsfield units) for the midline of the dorsal neural arch of the atlas in dogs with IODA was significantly lower than that for the same site in the dogs without IODA. The mean age at surgery for dogs with central IODA was significantly higher than that of the non-IODA group. The severity of spinal cord injury before or after atlantoaxial ventral fixation did not differ between the IODA and non-IODA groups.
CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that concomitant DAs or IODA is common in dogs with AAI. In dogs with incomplete ossification in the central part of the dorsal neural arch of the atlas, surgical treatment of AAI generally occurs at a middle to advanced age.
OBJECTIVE To determine brain region affinity for and retention of gadolinium in dogs after administration of gadodiamide and whether formalin fixation affects quantification.
ANIMALS 14 healthy dogs.
PROCEDURES 13 dogs received gadodiamide (range, 0.006 to 0.1 mmol/kg, IV); 1 control dog received a placebo. Dogs received gadodiamide 3 to 7 days (n = 8) or 9 hours (5) before euthanasia and sample collection. Brain regions were analyzed with inductively coupled mass spectrometry (ICP-MS) and transmission electron microscopy. Associations between dose, time to euthanasia, and gadolinium retention quantities (before and after fixation in 5 dogs) were evaluated.
RESULTS Gadolinium retention was seen in all brain regions at all doses, except for the control dog. Exposure 3 to 7 days before euthanasia resulted in 1.7 to 162.5 ng of gadolinium/g of brain tissue (dose-dependent effect), with cerebellum, parietal lobe, and brainstem affinity. Exposure 9 hours before euthanasia resulted in 67.3 to 1,216.4 ng of gadolinium/g of brain tissue without dose dependency. Transmission electron microscopy revealed gadolinium in examined tissues. Fixation did not affect quantification in samples immersed for up to 69 days.
CONCLUSIONS AND CLINICAL RELEVANCE Gadodiamide exposure resulted in gadolinium retention in the brain of healthy dogs. Cerebellum, parietal lobe, and brainstem affinity was detected with dose dependency only in dogs exposed 3 to 7 days before euthanasia. Fixation had no effect on quantification when tissues were immersed for up to 69 days. Physiologic mechanisms for gadolinium retention remained unclear. The importance of gadolinium retention requires further investigation.
OBJECTIVE To quantitatively analyze brain perfusion parameters in dogs with idiopathic epilepsy (IE) by use of MRI and to compare those findings with brain perfusion parameters for healthy dogs.
ANIMALS 12 client-owned dogs with IE.
PROCEDURES For each dog, standard MRI and perfusion-weighted imaging (before and after injection of gadoteric acid contrast medium) sequences of the brain were obtained during the interictal period by means of the same protocol used in a comparable study of healthy dogs. Time of contrast medium arrival, time to peak contrast enhancement, mean contrast transit time, and cerebral blood flow were calculated for the caudate nucleus, thalamus, piriform lobe, hippocampus, semioval center, and temporal cerebral cortex. Parameters for each structure were compared between dogs with IE and healthy dogs.
RESULTS Dogs with IE had a significantly greater mean time of contrast arrival and lower mean cerebral blood flow than healthy dogs. Differences in cerebral blood flow between dogs with IE and healthy dogs were most pronounced in the piriform lobe, thalamus, and temporal cerebral cortex. The mean contrast transit time did not differ between dogs with IE and healthy dogs.
CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that, compared with healthy dogs, dogs with IE have decreased blood perfusion of the brain. Findings of this study can be used as a basis for further research into functional changes within the brains of epileptic dogs during the interictal phase.
OBJECTIVE To investigate epilepsy-related neuropathologic changes in cats of a familial spontaneous epileptic strain (ie, familial spontaneous epileptic cats [FSECs]).
ANIMALS 6 FSECs, 9 age-matched unrelated healthy control cats, and 2 nonaffected (without clinical seizures)dams and 1 nonaffected sire of FSECs.
PROCEDURES Immunohistochemical analyses were used to evaluate hippocampal sclerosis, amygdaloid sclerosis, mossy fiber sprouting, and granule cell pathological changes. Values were compared between FSECs and control cats.
RESULTS Significantly fewer neurons without gliosis were detected in the third subregion of the cornu ammonis (CA) of the dorsal and ventral aspects of the hippocampus as well as the central nucleus of the amygdala in FSECs versus control cats. Gliosis without neuronal loss was also observed in the CA4 subregion of the ventral aspect of the hippocampus. No changes in mossy fiber sprouting and granule cell pathological changes were detected. Moreover, similar changes were observed in the dams and sire without clinical seizures, although to a lesser extent.
CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that the lower numbers of neurons in the CA3 subregion of the hippocampus and the central nucleus of the amygdala were endophenotypes of familial spontaneous epilepsy in cats. In contrast to results of other veterinary medicine reports, severe epilepsy-related neuropathologic changes (eg, hippocampal sclerosis, amygdaloid sclerosis, mossy fiber sprouting, and granule cell pathological changes) were not detected in FSECs. Despite the use of a small number of cats with infrequent seizures, these findings contributed new insights on the pathophysiologic mechanisms of genetic-related epilepsy in cats.
OBJECTIVE To compare the percentage of the C3-C7 vertebral canal occupied by the spinal cord in small-breed dogs with that in Doberman Pinschers and Great Danes with and without cervical spondylomyelopathy (CSM).
ANIMALS 30 small-breed dogs (body weight, < 15 kg), 15 clinically normal Doberman Pinschers, 15 Doberman Pinschers with CSM, 15 clinically normal Great Danes, and 15 Great Danes with CSM.
PROCEDURES In a retrospective study, sagittal and transverse T2-weighted MRI images of the cervical (C3 to C7) vertebral column obtained from dogs that met study criteria and were free of extensive abnormalities that could affect the spinal cord diameter between January 2005 and February 2015 were reviewed. The area and height of the vertebral column and spinal cord were measured at the cranial and caudal aspect of each vertebra from C3 to C7, and the percentage of the vertebral canal occupied by the spinal cord at each location was calculated and compared among groups of dogs.
RESULTS Mean percentage of the vertebral canal occupied by the spinal cord was greatest for small-breed dogs and lowest for Great Danes, but did not differ between Doberman Pinschers and small-breed dogs at approximately half of the locations evaluated or between Doberman Pinschers with and without CSM or between Great Danes with and without CSM.
CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the percentage of the vertebral canal occupied by the spinal cord, although expected to increase with vertebral canal stenosis, may not have a primary role in the pathogenesis of CSM.
OBJECTIVE To determine the physiochemical properties and pharmacokinetics of 3 midazolam gel formulations following buccal administration to dogs.
ANIMALS 5 healthy adult hounds.
PROCEDURES In phase 1 of a 2-phase study, 2 gel formulations were developed that contained 1% midazolam in a poloxamer 407 (P1) or hydroxypropyl methylcellulose (H1) base and underwent rheological and in vitro release analyses. Each formulation was buccally administered to 5 dogs such that 0.3 mg of midazolam/kg was delivered. Each dog also received midazolam hydrochloride (0.3 mg/kg, IV). There was a 3-day interval between treatments. Blood samples were collected immediately before and at predetermined times for 8 hours after drug administration for determination of plasma midazolam concentration and pharmacokinetic analysis. During phase 2, a gel containing 2% midazolam in a hydroxypropyl methylcellulose base (H2) was developed on the basis of phase 1 results. That gel was buccally administered such that midazolam doses of 0.3 and 0.6 mg/kg were delivered. Each dog also received midazolam (0.3 mg/kg, IV). All posttreatment procedures were the same as those for phase 1.
RESULTS The H1 and H2 formulations had lower viscosity, greater bioavailability, and peak plasma midazolam concentrations that were approximately 2-fold as high, compared with those for the P1 formulation. The mean peak plasma midazolam concentration for the H2 formulation was 187.0 and 106.3 ng/mL when the midazolam dose administered was 0.6 and 0.3 mg/kg, respectively.
CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that buccal administration of gel formulations might be a viable alternative for midazolam administration to dogs.
OBJECTIVE To compare ammonia concentrations in arterial blood, venous blood, and CSF samples of dogs with and without extrahepatic portosystemic shunts (EHPSS).
ANIMALS 19 dogs with congenital EHPSS and 6 healthy control dogs.
PROCEDURES All dogs underwent a physical examination and then were anesthetized for transsplenic portal scintigraphy to confirm the presence or absence of EHPSS. While dogs were anesthetized, arterial and venous blood samples and a CSF sample were simultaneously collected for determination of ammonia concentration, which was measured by use of a portable blood ammonia analyzer (device A) and a nonportable biochemical analyzer (device B). Results were compared between dogs with EHPSS and control dogs.
RESULTS Arterial, venous, and CSF ammonia concentrations for dogs with EHPSS were significantly greater than those for control dogs. For dogs with EHPSS, ammonia concentrations in both arterial and venous blood samples were markedly increased from the reference range. There was a strong positive correlation between arterial and venous ammonia concentrations and between blood (arterial or venous) and CSF ammonia concentrations.
CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that blood and CSF ammonia concentrations in dogs with EHPSS were greater than those for healthy dogs and were strongly and positively correlated, albeit in a nonlinear manner. This suggested that the permeability of the blood-brain barrier to ammonia may be abnormally increased in dogs with EHPSS, but further investigation of the relationship between blood or CSF ammonia concentration and clinical signs of hepatic encephalopathy or the surgical outcome for dogs with EHPSS is warranted.
OBJECTIVE To characterize CT findings and outcomes in dogs with head trauma and design a prognostic scale.
ANIMALS 27 dogs admitted to the Koret School Veterinary Teaching Hospital within 72 hours after traumatic head injury that underwent CT imaging of the head.
PROCEDURES Data were extracted from medical records regarding dog signalment, history, physical and neurologic examination findings, and modified Glasgow coma scale scores. All CT images were retrospectively evaluated by a radiologist unaware of dog status. Short-term (10 days after trauma) and long-term (≥ 6 months after trauma) outcomes were determined, and CT findings and other variables were analyzed for associations with outcome. A prognostic CT-based scale was developed on the basis of the results.
RESULTS Cranial vault fractures, parenchymal abnormalities, or both were identified via CT in 24 of 27 (89%) dogs. Three (11%) dogs had only facial bone fractures. Intracranial hemorrhage was identified in 16 (59%) dogs, cranial vault fractures in 15 (56%), midline shift in 14 (52%), lateral ventricle asymmetry in 12 (44%), and hydrocephalus in 7 (26%). Hemorrhage and ventricular asymmetry were significantly and negatively associated with short- and long-term survival, respectively. The developed 7-point prognostic scale included points for hemorrhage, midline shift or lateral ventricle asymmetry, cranial vault fracture, and depressed fracture (1 point each) and infratentorial lesion (3 points).
CONCLUSIONS AND CLINICAL RELEVANCE The findings reported here may assist in determining prognoses for other dogs with head trauma. The developed scale may be useful for outcome assessment of dogs with head trauma; however, it must be validated before clinical application.