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

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          Abstract

          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 wash-out 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 chromatography-tandem 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.

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          Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study

          The authors compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk.
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            Executive and prefrontal dysfunction in unipolar depression: a review of neuropsychological and imaging evidence.

            This paper reviews recent empirical findings related to prefrontal and executive function in unipolar depression. While a number of reviews have dealt with either the neuropsychological literature or findings from imaging studies, the present review addresses both, as well as findings from studies that have combined brain-imaging techniques with neuropsychological measures. This combined approach is of great interest as the performance of a structured task may act to load the areas of interest and reduce variance, thus making the imaging evidence more valuable; while the use of imaging provides a check that the neuropsychological tasks are indeed engaging the structures whose performance they are intended to assess. Prominent models of the neurobiology of depression implicate involvement of the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). The evidence from combined imaging and neuropsychological studies supports the involvement of the ACC, but is less clear in the case of the DLPFC. However, the limited number of such studies conducted to date means that conclusions must be tentative and further studies employing this combined approach may be of great value.
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              Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers.

              Ketamine is known to provide analgesic effects without an anesthetic when administered in a low dose. We previously reported that a tablet containing ketamine had analgesic effects in patients with neuropathic pain. In the present study, we compared the plasma concentration profiles of the enantiomers of ketamine and its active metabolite, norketamine, up to 8 h after the administration of 20 mg of ketamine by injection, after the administration of two tablets containing 25 mg of ketamine, after the administration of two sublingual tablets containing 25 mg of ketamine, after the insertion of a suppository containing 50 mg of ketamine, and after the application of a nasal spray containing 25 mg of ketamine to three healthy volunteers. The plasma concentration of ketamine biexponentially declined after the administration by injection; the value of T(1/2beta) for ketamine was approximately 120 min. The bioavailability of the tablet was estimated to be approximately 20%; the area under the plasma concentration-time curve, (AUC)(0-->8 h), of norketamine was approximately 500 ng h/ml in both enantiomers. The bioavailabilities of the sublingual tablet and the suppository were estimated to both be approximately 30%; the AUC(0-->8 h) of norketamine was 280-460 ng h/ml in both enantiomers. The plasma concentration profiles of the sublingual tablet and the suppository were almost similar to that of the tablet. The bioavailability of the nasal spray was estimated to be approximately 45%, which was the highest value among the preparations tested, and the AUC(0-->6 h) of norketamine was low (approximately 100 ng h/ml) in both enantiomers. These pharmacokinetic findings suggested that all of the ketamine preparations tested in this study may be useful for the alleviation of neuropathic pain. We propose that the type of ketamine preparation should be selected in accordance with the patient's disease condition and the required dosage amount of ketamine.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                13 January 2020
                2020
                : 15
                : 1
                : e0227762
                Affiliations
                [1 ] Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
                [2 ] Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
                [3 ] Department of Veterinary Medical Imaging and Small Animal Orthopaedics, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
                [4 ] Department of Psychiatry and Medical Psychology, Ghent Experimental Psychiatry (GHEP) lab, Ghent University, Ghent, Belgium
                [5 ] Biometrics Research Centre, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
                University of Bari, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-9625-9847
                http://orcid.org/0000-0003-2512-4176
                http://orcid.org/0000-0001-6357-3517
                http://orcid.org/0000-0002-9463-6442
                Article
                PONE-D-19-19289
                10.1371/journal.pone.0227762
                6957157
                31929589
                b9a8133a-cc43-4d31-b1f3-b1e0749ee21f
                © 2020 Vlerick et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 9 July 2019
                : 28 December 2019
                Page count
                Figures: 1, Tables: 3, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100007229, Bijzonder Onderzoeksfonds;
                Award ID: 01D26115
                Award Recipient :
                Funding for this study was provided by Special Research Fund Grant from the Ghent University ( https://www.ugent.be/nl/onderzoek/financiering/bof., No 01D26115, assigned to LV). The Ghent University had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Dogs
                Medicine and Health Sciences
                Pharmacology
                Sedation
                Medicine and Health Sciences
                Cardiology
                Heart Rate
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Sedatives
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Drug Administration
                Medicine and Health Sciences
                Pharmacology
                Routes of Administration
                Medicine and Health Sciences
                Pharmacology
                Pharmacokinetics
                Medicine and Health Sciences
                Pharmacology
                Routes of Administration
                Intranasal Administration
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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