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      A retrospective study of theophylline-based therapy with tracheal collapse in small-breed dogs: 47 cases (2013–2017)

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          Abstract

          Theophylline acts as a bronchodilator and has an anti-inflammatory effect. In addition, theophylline can be applied in patients where there are concerns regarding the side-effects of corticosteroids. This retrospective case series evaluated theophylline-based therapy in tracheal collapse (TC) canine patients. Forty-seven dogs with TC that received theophylline-based therapy during 2013–2017 were investigated. A fluoroscopic examination was performed to diagnose and grade TC. Theophylline was prescribed (7.5–30 mg/kg PO q12h) and the theophylline serum concentrations were measured. Coughing was assessed using a coughing scoring scale. The mean coughing score decreased after the theophylline-based therapy compared with that observed before treatment. Clinical improvements were observed in 46/47 patients (97.9%). As the intrathoracic TC grading increased, the final theophylline dosage also increased ( p value 0.019). The symptom-free period (SFP) with therapy was 189.7 ± 194.45 days (range, 0–720 days) and there was no statistically significant correlation between the SFP and age, sex, or TC grade on fluoroscopy. Although theophylline has generally been used as a third-line treatment, it was used as the main treatment in this study and most patients showed improvements. Dogs have a wider therapeutic index of serum concentrations than humans, and any undesirable effects were easily overcome. With further research, this therapy may prove to be a useful approach, but its safety for long-term use in the treatment of canine TC patients needs to be established.

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          Most cited references42

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          Theophylline.

          Theophylline (dimethylxanthine) has been used to treat airway diseases for more than 80 years. It was originally used as a bronchodilator, but the relatively high doses required are associated with frequent side effects, so its use declined as inhaled β2-agonists became more widely used. More recently it has been shown to have antiinflammatory effects in asthma and chronic obstructive pulmonary disease (COPD) at lower concentrations. The molecular mechanism of bronchodilatation is inhibition of phosphodiesterase (PDE)3, but the antiinflammatory effect may be due to inhibition of PDE4 and histone deacetylase-2 activation, resulting in switching off of activated inflammatory genes. Through this mechanism, theophylline also reverses corticosteroid resistance, and this may be of particular value in severe asthma and COPD, wherein histone deacetylase-2 activity is reduced. Theophylline is given systemically (orally as slow-release preparations for chronic treatment and intravenously for acute exacerbations of asthma). Efficacy is related to blood concentrations, which are determined mainly by hepatic metabolism, which may be increased or decreased in several diseases and by concomitant drug therapy. Theophylline is now usually used as an add-on therapy in patients with asthma not well controlled on inhaled corticosteroids with or without long-acting β2-agonists and in patients with COPD with severe disease not controlled by bronchodilator therapy. Side effects are related to plasma concentrations and include nausea, vomiting, and headaches due to PDE inhibition and at higher concentrations to cardiac arrhythmias and seizures due to adenosine A1-receptor antagonism. In the future, low-dose theophylline may be useful in reversing corticosteroid resistance in COPD and severe asthma.
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            A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression.

            The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.
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              Effects of a symptom-free waiting period on clinical outcome and risk of reinjury after sport-related concussion.

              This study is the first to investigate the influence of a symptom-free waiting period (SFWP) on clinical outcome and risk of repeat injury after sport-related concussion. This was a prospective, nonrandomized study of 16 624 player seasons from 1999 to 2004, including a cohort of 635 concussed high school and college athletes grouped on the basis of an SFWP or no SFWP observed after their concussion. Clinical outcome in symptoms, cognitive functioning, and postural stability 45 and 90 days postinjury was compared with preinjury baseline. Data on SFWP and same-season repeat concussion were recorded. An SFWP was observed in 60.3% of cases. There were no significant differences between the SFWP and no SFWP groups in acute injury characteristics or clinical outcome with respect to symptom recovery or postinjury performance on formal neuropsychological and balance testing. Most repeat concussions (79.2%) occurred within 10 days of the initial injury. The rate of repeat concussion was actually higher in the SFWP group (6.49%) than the no SFWP group (0.90%) (P < 0.005), but the repeat concussion subgroup's SFWP was 2.82 days shorter (95% confidence interval, 0.61-5.03; P < 0.01) and these athletes resumed participation 3.55 days sooner (95% confidence interval, 0.06-7.04; P < 0.05) than those in the SFWP group in which there was no repeat concussion. Our findings suggest that an SFWP did not intrinsically influence clinical recovery or reduce risk of a repeat concussion. The overall risk of same-season repeat concussion seems to be relatively low, but there may be a period of vulnerability that increases risk of repeat concussion during the first 7 to 10 days postinjury. Further study is required to investigate this preliminary finding and help determine whether this risk can be reduced further with specific injury-management strategies.
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                Author and article information

                Journal
                J Vet Sci
                J. Vet. Sci
                JVS
                Journal of Veterinary Science
                The Korean Society of Veterinary Science
                1229-845X
                1976-555X
                September 2019
                11 September 2019
                : 20
                : 5
                : e57
                Affiliations
                [1 ]Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.
                [2 ]Laboratory of Veterinary Radiology, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.
                Author notes
                Corresponding authors: Hwa-Young Youn. Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwankak-gu, Seoul 08826, Korea. hyyoun@ 123456snu.ac.kr
                Corresponding authors: Woo-Jin Song. Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwankak-gu, Seoul 08826, Korea. woojin1988@ 123456snu.ac.kr
                Author information
                https://orcid.org/0000-0002-5689-3608
                https://orcid.org/0000-0001-9563-6615
                https://orcid.org/0000-0002-0283-1348
                Article
                10.4142/jvs.2019.20.e57
                6769334
                31565900
                4aaa9221-39e8-4e99-a255-518f1a74b05a
                © 2019 The Korean Society of Veterinary Science

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 04 March 2019
                : 17 July 2019
                : 28 August 2019
                Funding
                Funded by: Seoul National University R&DB Foundation;
                Award ID: 550-20190090
                Categories
                Original Article
                Internal Medicine

                Veterinary medicine
                trachea collapse,small breed dogs,fluoroscopy,theophylline,symptom-free period
                Veterinary medicine
                trachea collapse, small breed dogs, fluoroscopy, theophylline, symptom-free period

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