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      Effectiveness of imepitoin for the control of anxiety and fear associated with noise phobia in dogs

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          Abstract

          Background

          Noise phobia is a common behavior problem in dogs for which there are limited treatment options.

          Objective

          To evaluate the efficacy and safety of imepitoin in comparison to placebo for the control of anxiety and fear associated with noise phobia in dogs.

          Animals

          Two hundred thirty‐eight client‐owned dogs with noise phobia were recruited in veterinary clinics.

          Methods

          This placebo‐controlled, randomized, double‐blinded, clinical trial used a predictable noise event as eliciting context, the traditional New Year's Eve fireworks in Germany and the Netherlands. Owners began treatment 2 days before the anticipated noise event with administration of either imepitoin 30 mg/kg body weight Q12h or placebo for 3 consecutive days. On New Year's Eve, owners noted their observations of their dog's fear and anxiety behavior at 1600, 2200, 0020, and 0100 hours and scored the overall treatment effect on the following day.

          Results

          In the 16‐item owner report of fear and anxiety signs, fear and anxiety behaviors were significantly reduced under imepitoin treatment compared to placebo (delta −6.1 scoring points; P < .0001). A significantly higher proportion of owners reported a good or excellent overall treatment effect in the imepitoin group compared to placebo (odds ratio 4.689; 95% CI, 2.79‐7.89; P < .0001).

          Conclusion

          Imepitoin effectively controls fear and anxiety associated with noise phobia in dogs.

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          Most cited references20

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          The ethics of placebo-controlled trials: methodological justifications.

          The use of placebo controls in clinical trials remains controversial. Ethical analysis and international ethical guidance permit the use of placebo controls in randomized trials when scientifically indicated in four cases: (1) when there is no proven effective treatment for the condition under study; (2) when withholding treatment poses negligible risks to participants; (3) when there are compelling methodological reasons for using placebo, and withholding treatment does not pose a risk of serious harm to participants; and, more controversially, (4) when there are compelling methodological reasons for using placebo, and the research is intended to develop interventions that can be implemented in the population from which trial participants are drawn, and the trial does not require participants to forgo treatment they would otherwise receive. The concept of methodological reasons is essential to assessing the ethics of placebo controls in these controversial last two cases. This article sets out key considerations relevant to considering whether methodological reasons for a placebo control are compelling. © 2013.
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            Anxioselective anxiolytics: on a quest for the Holy Grail.

            The discovery of benzodiazepine receptors provided the impetus to discover and develop anxioselective anxiolytics ('Valium without the side effects'). The market potential for an anxioselective based on the γ-aminobutyric acid A (GABA(A)) receptor resulted in clinical trials of multiple compounds. In contrast to the anxioselective profile displayed in preclinical models, compounds such as bretazenil, TPA023, and MRK 409 produced benzodiazepine-like side effects (sedation, dizziness) in Phase I studies, whereas alpidem and ocinaplon exhibited many of the characteristics of an anxioselective in the clinic. Alpidem was briefly marketed for the treatment of anxiety, but was withdrawn because of liver toxicity. Reversible elevations in liver enzymes halted development of ocinaplon in Phase III. The clinical profiles of these two molecules demonstrate that it is possible to develop GABA(A) receptor-based anxioselectives. However, despite the formidable molecular toolbox at our disposal, we are no better informed about the GABA(A) receptors responsible for an anxioselective profile in the clinic. Here, I discuss the evolution of a quest, spanning four decades, for molecules that retain the rapid and robust anti-anxiety actions of benzodiazepines without the side effects that limit their usefulness. Published by Elsevier Ltd.
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              The pharmacology of imepitoin: the first partial benzodiazepine receptor agonist developed for the treatment of epilepsy.

              Although benzodiazepines (BZDs) offer a wide spectrum of antiepileptic activity against diverse types of epileptic seizures, their use in the treatment of epilepsy is limited because of adverse effects, loss of efficacy (tolerance), and development of physical and psychological dependence. BZDs act as positive allosteric modulators of the inhibitory neurotransmitter GABA by binding to the BZD recognition site ("BZD receptor") of the GABAA receptor. Traditional BZDs such as diazepam or clonazepam act as full agonists at this site, so that one strategy to resolve the disadvantages of these compounds would be the development of partial agonists with lower intrinsic efficacy at the BZD site of the GABAA receptor. Several BZD site partial or subtype selective compounds, including bretazenil, abecarnil, or alpidem, have been developed as anxioselective anxiolytic drugs, but epilepsy was not a target indication for such compounds. More recently, the imidazolone derivatives imepitoin (ELB138) and ELB139 were shown to act as low-affinity partial agonists at the BZD site of the GABAA receptor, and imepitoin was developed for the treatment of epilepsy. Imepitoin displayed a broad spectrum of anticonvulsant activity in diverse seizure and epilepsy models at tolerable doses, and, as expected from its mechanism of action, lacked tolerance and abuse liability in rodent and primate models. The more favorable pharmacokinetic profile of imepitoin in dogs versus humans led to the decision to develop imepitoin for the treatment of canine epilepsy. Based on randomized controlled trials that demonstrated antiepileptic efficacy and high tolerability and safety in epileptic dogs, the drug was recently approved for this indication in Europe. Hopefully, the favorable profile of imepitoin for the treatment of epilepsy in dogs will reactivate the interest in partial BZD site agonists as new treatments for human epilepsy.
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                Author and article information

                Contributors
                odilo.engel@boehringer-ingelheim.com
                Journal
                J Vet Intern Med
                J. Vet. Intern. Med
                10.1111/(ISSN)1939-1676
                JVIM
                Journal of Veterinary Internal Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                0891-6640
                1939-1676
                30 September 2019
                Nov-Dec 2019
                : 33
                : 6 ( doiID: 10.1111/jvim.v33.6 )
                : 2675-2684
                Affiliations
                [ 1 ] Boehringer Ingelheim Vetmedica GmbH Ingelheim am Rhein Germany
                [ 2 ] Boehringer Ingelheim Pharma GmbH & Co.KG Ingelheim am Rhein Germany
                [ 3 ] Animal Behaviour Cognition and Welfare Group, School of Life Sciences University of Lincoln Lincoln United Kingdom
                Author notes
                [*] [* ] Correspondence

                Odilo Engel, Boehringer Ingelheim Vetmedica GmbH, Binger Str. 173, 55216 Ingelheim am Rhein, Germany.

                Email: odilo.engel@ 123456boehringer-ingelheim.com

                Author information
                https://orcid.org/0000-0002-6160-3281
                Article
                JVIM15608
                10.1111/jvim.15608
                6872611
                31568622
                427b20c8-5188-44de-a294-4c93c25c4509
                © 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 20 February 2019
                : 20 August 2019
                Page count
                Figures: 5, Tables: 4, Pages: 10, Words: 6534
                Funding
                Funded by: Boehringer Ingelheim
                Categories
                Standard Article
                SMALL ANIMAL
                Standard Articles
                Neurology
                Custom metadata
                2.0
                jvim15608
                November/December 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.7.2 mode:remove_FC converted:21.11.2019

                Veterinary medicine
                anxiolytic,clinical trial,firework,imepitoin,noise aversion,noise phobia,noise sensitivity

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