Pharmacokinetics, absolute bioavailability and tolerability of ketamine after intranasal administration to dexmedetomidine sedated dogs

Intranasal ketamine has recently gained interest in human medicine, not only for its sedative, anaesthetic or analgesic properties, but also in the management of treatment resistant depression, where it has been shown to be an effective, fast acting alternative treatment. Since several similarities are reported between human psychiatric disorders and canine anxiety disorders, intranasal ketamine could serve as an alternative treatment for anxiety disordered dogs. However, to the authors knowledge, intranasal administration of ketamine and its pharmacokinetics have never been described in dogs. Therefore, this study aimed to examine the pharmacokinetics, absolute bioavailability and tolerability of intranasal ketamine administration compared with intravenous administration. Seven healthy, adult laboratory Beagle dogs were included in this randomized crossover study. The dogs received 2 mg/kg body weight ketamine intravenously (IV) or intranasally (IN), with a two-week washout period. Prior to ketamine administration, dogs were sedated intramuscularly with dexmedetomidine. Venous blood samples were collected at fixed times until 480 min post-administration and ketamine plasma concentrations were determined by liquid chromatographytandem mass spectrometry. Cardiovascular parameters and sedation scores were recorded at the same time points. Non-compartmental pharmacokinetic analysis revealed a rapid (Tmax = 0.25 +/- 0.14 h) and complete IN bioavailability (F = 147.65 +/- 49.97%). Elimination half-life was similar between both administration routes (T1/2el IV = 1.47 +/- 0.24 h, T1/2el IN = 1.50 +/- 0.97 h). Heart rate and sedation scores were significantly higher at 5 and 10 min following IV administration compared to IN administration, but not at the later time-points

The long-term effects of single and repeated subanaesthetic ketamine administration on regional cerebral blood flow in healthy dogs measured with 99mTc-HMPAO SPECT

Subanaesthetic ketamine has recently been established as an effective and rapid treatment for major depressive disorder showing antidepressant effects for up to 1 week on average. The use of repeated ketamine infusions has been put forward to augment and to prolong the antidepressant response and increase the remission rates. The underlying neurobiological mechanisms responsible for ketamine's antidepressant effects remain unclear. Nevertheless, it has been shown, both in dogs and humans, that ketamine can alter neuronal perfusion and therefore neuronal function in brain regions involved in psychiatric and behavioural disorders. Consequently, the aim of the current placebo controlled study was to assess the long-term effects on cerebral perfusion of single and repeated subanaesthetic ketamine infusions in dogs. Twelve healthy, laboratory dogs were scanned at six different time points following single and repeated ketamine administration, using Single Photon Emission Computed Tomography with the radiotracer Tc-99m-hexamethylpropylene amine oxime. We hypothesised that repeated infusions could lead to more prolonged perfusion alterations in brain regions critical for behaviour regulation. We found that repeated subanaesthetic ketamine administration did not result in more prolonged cerebral perfusion alterations compared to a single ketamine administration

The influence of subanaesthetic ketamine on regional cerebral blood flow in healthy dogs measured with 99mTc-HMPAO SPECT

Subanaesthetic ketamine has recently been proven to be a highly effective and fast acting alternative treatment for several psychiatric disorders. The mechanisms responsible for ketamine's antidepressant effects remain unclear, but a possible explanation could be that ketamine interacts with regional cerebral blood flow (rCBF). Therefore, the effects of two subanaesthetic ketamine doses on rCBF were evaluated. Twelve dogs were randomly assigned to one of the three treatment conditions (condition saline, condition 0.5 mg/kg ketamine or condition 2 mg/kg ketamine) and received in total five saline or ketamine infusions, with one week interval. Single Photon Emission Computed Tomography (SPECT) scans with the radiotracer Tc-99m-hexamethylpropylene amine oxime were performed before the start of the infusions (baseline) and 24 hours after the first (single) and last (multiple) infusion. After a wash out period of 3 months, the animals were again assigned to one of the three treatment conditions described above and the infusion/scan protocol was repeated. During the infusions, cardiovascular parameters were evaluated every ten minutes. A one-way repeated measure ANOVA was set up to assess perfusion index for each ketamine dose for the left frontal cortex (alpha = 0.05). The remaining 11 brain regions were post hoc assessed. Perfusion index was significantly increased in the left frontal cortex and in the thalamus 24 hours after single and multiple ketamine infusions compared to baseline in the 2 mg/kg condition. No clinically relevant cardiovascular effects were observed during the ketamine infusions. This study shows that subanaesthetic ketamine can increase neuronal perfusion and therefore alter neuronal function in brain regions involved in depression and anxiety disorders. These perfusion increases may possibly contribute to ketamine's beneficial effects in these psychiatric disorders

Accurate external localization of the left frontal cortex in dogs by using pointer based frameless neuronavigation

Background. In humans, non-stereotactic frameless neuronavigation systems are used as a topographical tool for non-invasive brain stimulation methods such as Transcranial Magnetic Stimulation (TMS). TMS studies in clogs may provide treatment modalities for several neuropsychological disorders in dogs. Nevertheless, an accurate non-invasive localization of a stimulation target has not yet been performed in this species. Hypothesis. This study was primarily put forward to externally locate the left frontal cortex in 18 healthy dogs by means of a human non-stereotactic neuronavigation system. Secondly, the accuracy of the external localization was assessed. Animals. A total of 18 healthy dogs, drawn at random from the research colony present at the faculty of Veterinary Medicine (Ghent University), were used. Methods. Two sets of coordinates (X, Y, Z and X", Y", Z") were compared on each dog their tornographical dataset. Results. The non-stereotactic neuronavigation system was able to externally locate the frontal cortex in dogs with accuracy comparable with human studies. Conclusion and clinical importance. This result indicates that a non-stereotactic neuronavigation system can accurately externally locate the left frontal cortex and paves the way to use guided non-invasive brain stimulation methods as an alternative treatment procedure for neurological and behavioral disorders in dogs. This technique could, in analogy with human guided non-invasive brain stimulation, provide a better treatment outcome for dogs suffering from anxiety disorders when compared to its non-guided alternative

PET quantification of [18F]MPPF in the canine brain using blood input and reference tissue modelling

Numerous studies have shown that the serotonin(1A) (5-HT1A) receptor is implicated in the pathophysiology and treatment of several psychiatric and neurological disorders. Furthermore, functional imaging studies in a variety of species have demonstrated that 4-(2'-Methoxyphenyl)-1-[2'-(N-2 ''-pyridinyl)-p-[F-18]fluorobenzamidoethylpiperazine ([F-18]MPPF) is a valid and useful PET tracer to visualize the 5HT(1A) receptor. However, to our knowledge, [F-18] MPPF has never been demonstrated in the canine brain. The ability to image the 5HT(1A) receptor with PET in dogs could improve diagnosis and therapy in both canine and human behavioural and neuropsychiatric disorders. To examine the potential use of [F-18]MPPF in dogs, five healthy adult laboratory beagles underwent a 60-minutes dynamic PET scan with [F-18]MPPF while arterial blood samples were taken. For each region of interest, total distribution volume (V-T) and corresponding binding potential (BPND) were calculated using the 1-tissue compartment model (1-TC), 2-Tissue compartment model (2-TC) and Logan plot. The preferred model was chosen based on the goodness-of-fit, calculated with the Akaike information criterium (AIC). Subsequently, the BPND values of the preferred compartment model were compared with the estimated BPND values using three reference tissue models (RTMs): the 2-step simplified reference tissue model (SRTM2), the 2-parameter multilinear reference tissue model (MRTM2) and the Logan reference tissue model. According to the lower AIC values of the 2-TC model compared to the 1-TC in all ROIs, the 2-TC model showed a better fit. Calculating BPND using reference tissue modelling demonstrated high correlation with the BPND obtained by metabolite corrected plasma input 2-TC. This first-indog study indicates the results of a bolus injection with [F-18] MPPF in dogs are consistent with the observations presented in the literature for other animal species and humans. Furthermore, for future experiments, compartmental modelling using invasive blood sampling could be replaced by RTMs, using the cerebellum as reference region

Estimation of the optimal dosing regimen of escitalopram in dogs : a dose occupancy study with [11C]DASB

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i. v. injection 0.83 mg/ kg. Blood samples were taken up to 12 hours after i. v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended