Objective—To compare the pharmacokinetics of a novel bioadhesive gel formulation of midazolam after intranasal (IN) administration with that of midazolam solution after IN, IV, and rectal administration to dogs.
Animals—10 (5 males and 5 females) healthy adult Beagles.
Procedures—Dogs were assigned to 4 treatment groups for a crossover study design. Initially, midazolam solution (5 mg/mL) was administered (0.2 mg/kg) IV to group 1, rectally to group 2, and IN to group 3; a 0.4% hydroxypropyl methylcellulose midazolam gel formulation (50 mg/mL) was administered (0.2 mg/kg, IN) to group 4. Each dog received all 4 treatments; there was a 7-day washout period between subsequent treatments. Blood samples were collected before and after midazolam administration. Plasma concentration of midazolam was determined by use of high-performance liquid chromatography.
Results—The peak plasma concentration after IN administration of the gel formulation was significantly higher than that after IN and rectal administration of the solution. Mean ± SD time to peak concentration was 11.70 ± 2.63 minutes (gel IN), 17.50 ± 2.64 minutes (solution IN), and 39 ± 14.49 minutes (solution rectally). Mean bioavailability of midazolam was 70.4% (gel IN), 52.0% (solution IN), and 49.0% (solution rectally). Bioavailability after IN administration of the gel formulation was significantly higher than that after IN and rectal administration of the solution.
Conclusions and Clinical Relevance—IN administration of midazolam gel was superior to both IN and rectal administration of midazolam solution with respect to peak plasma concentration and bioavailability.
Objective—To objectively describe morphometric features of the craniocervical junction region of Cavalier King Charles Spaniels (CKCSs) and non-CKCS dogs with suspected Chiari-like malformation (CLM) and identify associations between these features and the presence of other malformations in this region.
Animals—216 CKCSs and 58 non-CKCS dogs.
Procedures—Magnetic resonance and computed tomographic images of the head and craniocervical junction region of patients evaluated because of suspected CLM were assessed for cerebellar compression (CC), ventral spinal cord compression at the C1–C2 articulation (medullary kinking), and dorsal spinal cord compression at the C1–C2 articulation (dorsal compression). A compression index was calculated for each of these 3 locations in each dog. Multiple logistic regression analysis was performed to determine whether breed (CKCS vs non-CKCS) and compression index values were associated with the presence of other craniocervical junction abnormalities.
Results—All 274 dogs had CC; medullary kinking was identified in 187 (68.2%) and dorsal compression was identified in 104 (38.0%). Atlantooccipital overlapping (AOO) was identified in 76 (27.7%) dogs. Breed of dog (CKCS vs non-CKCS) and value of CC index were the only significant predictors of AOO. The CKCSs had an almost 5-fold decrease in risk of AOO, compared with the non-CKCS dogs, and the risk of AOO nearly doubled for every 10% increase in CC index.
Conclusions and Clinical Relevance—The anatomic abnormality responsible for CC was AOO in a substantial percentage of dogs suspected to have CLM. The CC index value may be used to help differentiate subtypes of craniocervical junction abnormalities in dogs.
Objective—To determine magnetic resonance imaging (MRI) vertebral ratio values representing vertebral canal height, vertebral canal shape, and vertebral body shape in Doberman Pinschers with and without disk-associated cervical spondylomyelopathy (DACSM) and clinically normal English Foxhounds.
Animals—Doberman Pinschers with (n = 18) and without (20) DACSM and clinically normal English Foxhounds (18).
Procedures—All dogs underwent low-field MRI of the cervical vertebral column. From 5 specific measurements made at C3 through C7, 4 linear vertebral ratios were calculated and assessed for correlation: vertebral canal height-to-body height ratio (CBHR), vertebral canal height-to-body length ratio (CBLR), caudal canal height-to-cranial canal height ratio (CCHR), and vertebral body length-to-height ratio (BLHR). The CBHR and CBLR described vertebral canal height, CCHR described vertebral canal shape, and BLHR described vertebral body shape. A midvertebral canal-occupying ratio (mVCOR) for the spinal cord was calculated at C5.
Results—Compared with both groups of unaffected dogs, CBHR, CBLR, and BLHR for Doberman Pinschers with DACSM were significantly smaller. The C7 CCHR was significantly larger in DACSM-affected Doberman Pinschers, compared with clinically normal English Foxhounds. Ratios did not differ significantly between unaffected Doberman Pinschers and clinically normal English Foxhounds. Correlation coefficients between CBHR, CBLR, and mVCOR were low and not significant.
Conclusions and Clinical Relevance—Doberman Pinschers with DACSM had significantly smaller vertebral canal heights and more square-shaped vertebral bodies, compared with unaffected Doberman Pinschers, combined with a funnel-shaped vertebral canal at C7. Breed-specific differences were not evident. Linear MRI vertebral canal-to-body ratios do not appear to predict relative vertebral canal stenosis.
Objective—To determine whether therapeutic concentrations of levetiracetam can be achieved in cats and to establish reasonable IV and oral dosing intervals that would not be associated with adverse effects in cats.
Animals—10 healthy purpose-bred cats.
Procedures—In a randomized crossover study, levetiracetam (20 mg/kg) was administered orally and IV to each cat. Blood samples were collected 0, 10, 20, and 40 minutes and 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours after administration. Plasma levetiracetam concentrations were determined via high-performance liquid chromatography.
Results—Mean ± SD peak concentration was 25.54 ± 7.97 μg/mL. The mean y-intercept for IV administration was 37.52 ± 6.79 μg/mL. Half-life (harmonic mean ± pseudo-SD) was 2.95 ± 0.95 hours and 2.86 ± 0.65 hours for oral and IV administration, respectively. Mean volume of distribution at steady state was 0.52 ± 0.09 L/kg, and mean clearance was 2.0 ± 0.60 mL/kg/min. Mean oral bioavailability was 102 ± 39%. Plasma drug concentrations were maintained in the therapeutic range reported for humans (5 to 45 μg/mL) for at least 9 hours after administration in 7 of 10 cats. Only mild, transient hypersalivation was evident in some cats after oral administration.
Conclusions and Clinical Relevance—Levetiracetam (20 mg/kg) administered orally or IV to cats every 8 hours should achieve and maintain concentrations within the therapeutic range for humans. Levetiracetam administration has favorable pharmacokinetics for clinical use, was apparently tolerated well, and may be a reasonable alternative antiepileptic drug in cats.
Objective—To determine radiographic vertebral ratio values representing vertebral canal stenosis in Doberman Pinschers with and without clinical signs of caudal cervical spondylomyelopathy (CCSM).
Animals—Doberman Pinschers with (n = 81) and without (39) signs of CCSM.
Procedures—All dogs underwent lateral survey radiography of the cervical vertebral column. Five specific measurements were made at C3 through C7, and from those data, 3 ratios were calculated and analyzed for use in diagnosis of CSSM: canal height-to-vertebral body height ratio (CBHR), canal height-to-vertebral body length ratio (CBLR), and caudal vertebral canal height-to-cranial vertebral canal height ratio (CCHR). The CBHR and CBLR were considered indicators of vertebral canal stenosis, and CCHR described vertebral canal shape.
Results—Compared with Doberman Pinschers without CCSM, mean CBHR and CBLR values were significantly smaller for Doberman Pinschers with CCSM; for CBHR, this difference was evident at each assessed vertebra. The CCHR value for C7 was significantly larger in dogs with CCSM. Receiver operating characteristic statistics did not identify a threshold point that had combined high sensitivity and specificity sufficient to differentiate between Doberman Pinschers with and without CCSM.
Conclusions and Clinical Relevance—Doberman Pinschers with CCSM had vertebral canal stenosis combined with a funnel-shaped vertebral canal at C7 significantly more often than did Doberman Pinschers without CCSM. Despite these significant differences, no reliable threshold ratio values were identified to differentiate groups of dogs.
Objective—To characterize the electroencephalogram (EEG) in young cats.
Animals—23 clinically normal cats.
Procedures—Cats were sedated with medetomidine hydrochloride and butorphanol tartrate at 2, 4, 6, 8, 12, 16, 20, and 24 weeks of age, and an EEG was recorded at each time point. Recordings were visually inspected for electrical continuity, interhemispheric synchrony, amplitude and frequency of background electrical activity, and frequency of transient activity. Computer-aided analysis was used to perform frequency spectral analysis and to calculate absolute and relative power of the background activity at each age.
Results—Electrical continuity was evident in cats ≥ 4 weeks old, and interhemispheric synchrony was evident in cats at all ages evaluated. Analysis of amplitude of background activity and absolute power revealed significant elevations in 6-week-old cats, compared with results for 2-, 20-, and 24-week-old cats. No association between age and relative power or frequency was identified. Transient activity, which consisted of sleep spindles and K complexes, was evident at all ages, but spike and spike-and-wave discharges were observed in cats at 2 weeks of age.
Conclusions and Clinical Relevance—Medetomidine and butorphanol were administered in accordance with a sedation protocol that allowed investigators to repeatedly obtain EEG data from cats. Age was an important consideration when interpreting EEG data. These data on EEG development in clinically normal cats may be used for comparison in future studies conducted to examine EEGs in young cats with diseases that affect the cerebral cortex.
Objective—To compare electroencephalography (EEG) artifact associated with use of the subdermal wire electrode (SWE), gold cup electrode (GCE), and subdermal needle electrode (SNE) over an 8-hour period in sedated and awake dogs.
Animals—6 healthy dogs.
Procedures—8 EEG channels were recorded during 20-minute video-EEG recording sessions (intermittently at 0.5, 2, 4, 6, and 8 hours) with and without chlorpromazine sedation. Nonphysiologic artifacts were identified. Duration of artifact was summed for each channel. Number of unaffected channels (NUC) was determined.
Results—NUC was significantly affected by electrode type and sedation over time; median for SWE (2.80 channels; 95% confidence interval [CI], 0.84 to 5.70 channels) was significantly different from medians for GCE (7.87 channels; 95% CI, 7.44 to 7.94 channels) and SNE (7.60 channels; 95% CI, 6.61 to 7.89 channels). After 4 hours, NUC decreased in awake dogs, regardless of electrode type. In awake dogs, duration of artifact differed significantly between SWE and GCE or SNE; medians at 8 hours were 61.55 seconds (95% CI, 21.81 to 173.65 seconds), 1.33 seconds (95% CI, 0.47 to 3.75 seconds), and 21.01 seconds (95% CI, 6.85 to 64.42 seconds), respectively.
Conclusions and Clinical Relevance—The SWE had a significant duration of artifact during recording periods > 2 hours, compared with results for the GCE and SNE, in awake dogs. The GCE, SNE, and sedation resulted in significantly more channels unaffected by artifact. For longer recordings, caution should be exercised in selecting EEG electrodes and sedation state, although differences among electrodes may not be clinically relevant.
Objective—To characterize the intracranial pressure-volume relationship (ICPVR) in dogs by use of an acute frontal-parietal mass lesion model.
Animals—7 healthy adult female Beagles.
Procedures—Dogs were anesthetized with isoflurane to achieve a surgical plane of anesthesia. A fiberoptic intracranial pressure (ICP) monitor was inserted to a depth of 1 cm in the parenchyma of the right frontal-parietal region of the brain. A Foley balloon-tipped catheter was placed in the epidural space of the left frontal-parietal area through a separate 1-cm burr hole. Baseline measurements were obtained with the balloon deflated. The balloon was then inflated incrementally with 0.5 mL of 0.9% NaCl solution every 10 minutes until ICP exceeded mean arterial blood pressure. Nonlinear regression analysis with 2-factor and 3-factor exponential equations was used to characterize the ICPVR.
Results—The mean baseline ICP was 11 mm Hg, with a 95% confidence interval of 2 to 20 mm Hg. The ICPVR was well characterized by 2-factor or 3-factor exponential equations for all dogs (R2 > 0.93). Balloon volumes of > 1. 2 mL were associated with ICP > 20 mm Hg.
Conclusions and Clinical Relevance—Characterization of the ICPVR may provide clinically useful information regarding the safety of obtaining CSF from the atlanto-occipital space or implantation of brachytherapy catheters and for determining the need for decompressive craniectomy in dogs with acute intracranial disease. High ICP should be suspected in dogs that have an acute frontal-parietal mass lesion estimated to exceed 2% of the brain volume.
Objective—To evaluate a technique for minimally invasive excisional brain biopsy and intracranial brachytherapy catheter placement in dogs.
Animals—5 healthy adult female dogs.
Procedures—Computed tomographic guidance was used to plan a biopsy trajectory to a selected area of brain with reference to a localizer grid. The procedure was performed through a 1-cm skin incision and 6-mm burr hole by use of a 9-gauge biopsy device. Five cylindrical samples (3 to 4 mm in diameter and 7 to 12 mm in length) were removed over 5 cycles of the vacuum-assisted tissue excision system, leaving approximately a 2-cm3 resection cavity. A balloon-tipped intracranial brachytherapy catheter was placed through the burr hole into the resection cavity, expanded with saline (0.9% NaCl) solution, and explanted 7 days later.
Results—4 of 5 dogs survived the procedure. The fifth died because of iatrogenic brain damage. Neurologic deficits were unilateral and focal. Twenty-four hours after surgery, all surviving dogs were ambulatory, 2 dogs exhibited ipsiversive circling, 4 had contralateral proprioceptive deficits, 3 had contralateral menace response deficits, 2 had a reduced contralateral response to noxious nasal stimulation, and 1 had dull mentation with intermittent horizontal nystagmus and ventrolateral strabismus. Neurologic status improved throughout the study period. Histologic quality of biopsy specimens was excellent.
Conclusions and Clinical Relevance—This technique enabled histologic diagnosis from high-quality biopsy specimens obtained through a minimally invasive technique and has potential applications for multimodal treatment of deep brain tumors in dogs.
Objective—To elucidate the pathogenesis of Greyhound meningoencephalitis by evaluating gene expression in diseased brain tissue.
Animals—Cadavers of 3 diseased (8- to 15-month-old) and 3 (10-month-old) control Greyhounds.
Procedures—Samples of RNA were extracted from brain tissue of all dogs and evaluated by use of a canine-specific microarray.
Results—A unique profile involving significant alterations in expression of 21 genes was evident in diseased dogs, compared with expression in control dogs. Most genes with up-regulated expression were related to immune function, with the remaining genes involved in ligand binding, signal transduction, transcriptional regulation, and formation and transportation of proteins including enzymes. Of notable involvement were genes encoding for major histocompatibility complexes, small inducible cytokine A5 precursor, myxovirus-resistant proteins, and components of the classical complement pathway, which are all genes common to pathways of viral infections and autoimmunity.
Conclusions and Clinical Relevance—Although results of microarray analysis did not clearly define a potential etiology of Greyhound meningoencephalitis, they did highlight a consistent gene alteration signature that would suggest a common etiology and pathogenesis for this condition.