Combretastatin A4-Phosphate (CA4P) is a vascular disrupting agent revealing promising results in cancer treatments for humans. The aim of this study was to investigate the safety and adverse events of CA4P in healthy dogs as a prerequisite to application of CA4P in dogs with cancer.Ten healthy dogs were included. The effects of escalating doses of CA4P on physical, haematological and biochemical parameters, systolic arterial blood pressure, electrocardiogram, echocardiographic variables and general wellbeing were characterised. Three different doses were tested: 50, 75 and 100 mg m −2 .At all 3 CA4P doses, nausea, abdominal discomfort as well as diarrhoea were observed for several hours following administration. Likewise, a low-grade neutropenia was observed in all dogs. Doses of 75 and 100 mg m −2 additionally induced vomiting and elevation of serum cardiac troponine I levels. At 100 mg m −2 , low-grade hypertension and high-grade neurotoxicity were also observed.In healthy dogs, doses up to 75 mg m −2 seem to be well tolerated. The severity of the neurotoxicity observed at 100 mg m −2 , although transient, does not invite to use this dose in canine oncology patients. K E Y W O R D Santicancer therapy, combretastatin A4-phosphate, dogs, dose-escalation, vascular disrupting agent
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.
BackgroundIn 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 dogs 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.HypothesisThis 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.AnimalsA total of 18 healthy dogs, drawn at random from the research colony present at the faculty of Veterinary Medicine (Ghent University), were used.MethodsTwo sets of coordinates (X, Y, Z and X″, Y″, Z″) were compared on each dog their tomographical dataset.ResultsThe non-stereotactic neuronavigation system was able to externally locate the frontal cortex in dogs with accuracy comparable with human studies.Conclusion and clinical importanceThis 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.
BackgroundCurrently, the rat has been a useful animal model in brain stimulation research. Nevertheless, extrapolating results from rodent repetitive Transcranial Magnetic Stimulation (rTMS) research to humans contains several hurdles. This suggests the desperate need for a large animal model in translational rTMS research. The dog would be a valid choice, not only due to the fact that humans and dogs share a neurophysiological background, but a similar neuropathological background as well.HypothesisIn order to evaluate the feasibility of the canine rTMS animal model, this study aimed to evaluate the neurophysiological response in dogs on a, clinically used, accelerated high frequency (aHF) rTMS protocol. This aHF-rTMS (20 Hz) protocol was performed under anaesthesia or sedation and either 20 sessions or 5 sessions were given to each dog.Methods21 healthy dogs were randomly subjected to one of the four aHF-rTMS protocols (1 sham and 3 active protocols). For each dog, the perfusion indices (PI), of a [99mTc]HMPAO scan at 4 time points, for the left frontal cortex (stimulation target) were calculated for each protocol.ResultsConcerning sham stimulation, the average PI remained at the baseline level. The main result was the presence of a direct transitory increase in rCBF at the stimulation site, both under anaesthesia and sedation. Nevertheless the measured increase in rCBF was higher but shorter duration under sedation. The magnitude of this increase was not influenced by number of sessions. No changes in rCBF were found in remote brain regions.ConclusionThis study shows that, despite the influence of anaesthesia and sedation, comparable and clinically relevant effects on the rCBF can be obtained in dogs. Since less methodological hurdles have to be overcome and comparable results can be obtained, it would be acceptable to put the dog forward as an alternative translational rTMS animal model.
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