Comparison of effects of dexamethasone and the leukotriene D4 receptor antagonist L-708,738 on lung function and airway cytologic findings in horses with recurrent airway obstruction.
Abstract: To evaluate whether the leukotriene (LT) D4 receptor antagonist L-708,738 is therapeutically beneficial in treating horses with recurrent airway obstruction (heaves). Methods: 12 adult horses with heaves and healthy lung lobes from 20 slaughtered horses. Methods: Lung lobes were used for smooth muscle tension and radioligand binding studies. Horses with heaves were given a placebo for 14 days and administered L-708,738 (n = 6; 2.5 mg/kg PO, q 12 h) or dexamethasone (6; 0.04 mg/kg, IV, q 24 h) from days 14 to 28. Pulmonary function was measured weekly for 36 days, and bronchoalveolar cells were collected on days 0,14, and 29 for cytologic examination. Results: Nanomolar concentrations of L-708,738 were effective at antagonizing LTD4-induced bronchoconstriction and LTD4-receptor binding in lung lobes. Mean peak and trough L708,738 plasma concentrations during the treatment period were 1.54 and 0.28 microM, respectively. On days 21 and 29, lung mechanics were significantly improved in the dexamethasone-treated horses but not in the L-708,738-treated horses. Neither dexamethasone nor L-708,738 had a significant effect on cytologic findings. Conclusions: L-708,738 was bioavailable after oral administration and sustained concentrations in plasma during the dosing period that exceeded in vitro efficacy values. However, airway function did not improve, suggesting that either drug concentrations in the lungs were subtherapeutic or that cysteinyl LT may not be important mediators of airway inflammation in heaves. Results provide the first evidence of cysteinyl LT1 receptors in airways of horses.
Publication Date: 2002-04-10 PubMed ID: 11939323DOI: 10.2460/ajvr.2002.63.579Google Scholar: Lookup
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- Comparative Study
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The study is essentially comparing the effects and potential therapeutic benefits of two drugs, dexamethasone and L-708,738, on horses suffering from recurrent airway obstruction, commonly known as heaves. The authors find that dexamethasone more significantly improves lung function in these horses, but neither drug significantly impacts airway cytology.
Study Design and Methods
- The researchers used a sample size of 12 adult horses diagnosed with recurrent airway obstruction.
- Lung lobes from 20 healthy slaughtered horses were also used for smooth muscle tension studies and radioligand binding studies.
- The 12 horses with heaves were administered a placebo for the first 14 days. After this, they were split into two groups – six were administered L-708,738 and the other six were given dexamethasone.
- Pulmonary function was measured once a week for 36 days. Additionally, bronchoalveolar cells were collected on days 0, 14, and 29 for cytologic examination.
Results and Findings
- The research found that nanomolar concentrations of L-708,738 were successful in combatting the bronchoconstriction induced by Leukotriene (LT) D4, a fatty molecule in the immune system associated with inflammation.
- However, when it came to improving the mechanics of the lung in heave-ridden horses, dexamethasone yielded significantly improved results compared to L-708,738.
- No significant effects on the cytologic findings were found, regardless of whether the horses were administered dexamethasone or L-708,738.
Conclusions
- L-708,738 was easily absorbed after oral administration and was found in plasma concentrations greater than in vitro efficacy values, which makes the drug bioavailable and therapeutically promising.
- Contrarily, despite this bioavailability, L-708,738 did not facilitate improvements in airway function. This implied that either the dosage of the drug wasn’t sufficient or that cysteinyl leukotriene D4, despite theoretical suggestions, might not have a significant role in mediating airway inflammation in heaves.
- The study, however, does provide the first evidence of cysteinyl leukotriene receptors in the airways of horses.
Cite This Article
APA
Lavoie JP, Léguillette R, Pasloske K, Charette L, Sawyer N, Guay D, Murphy T, Hickey GJ.
(2002).
Comparison of effects of dexamethasone and the leukotriene D4 receptor antagonist L-708,738 on lung function and airway cytologic findings in horses with recurrent airway obstruction.
Am J Vet Res, 63(4), 579-585.
https://doi.org/10.2460/ajvr.2002.63.579 Publication
Researcher Affiliations
- Department of Clinical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, St Hyacinthe, QC, Canada.
MeSH Terms
- Airway Obstruction / drug therapy
- Airway Obstruction / veterinary
- Animals
- Anti-Inflammatory Agents, Non-Steroidal / blood
- Anti-Inflammatory Agents, Non-Steroidal / pharmacology
- Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
- Binding, Competitive
- Bronchoalveolar Lavage Fluid / cytology
- Dexamethasone / blood
- Dexamethasone / pharmacology
- Horse Diseases / drug therapy
- Horse Diseases / physiopathology
- Horses
- In Vitro Techniques
- Leukotriene Antagonists / blood
- Leukotriene Antagonists / pharmacology
- Leukotriene D4 / metabolism
- Muscle Contraction / drug effects
- Muscle, Smooth / drug effects
- Muscle, Smooth / physiopathology
- Respiratory Function Tests / veterinary
Citations
This article has been cited 16 times.- Klier J, Fuchs S, Winter G, Gehlen H. Inhalative Nanoparticulate CpG Immunotherapy in Severe Equine Asthma: An Innovative Therapeutic Concept and Potential Animal Model for Human Asthma Treatment.. Animals (Basel) 2022 Aug 16;12(16).
- Mainguy-Seers S, Lavoie JP. Glucocorticoid treatment in horses with asthma: A narrative review.. J Vet Intern Med 2021 Jul;35(4):2045-2057.
- Dixon CE, Bedenice D, Mazan MR. Comparison of Flowmetric Plethysmography and Forced Oscillatory Mechanics to Measure Airway Hyperresponsiveness in Horses.. Front Vet Sci 2020;7:511023.
- Pirie RS, Mueller HW, Engel O, Albrecht B, von Salis-Soglio M. Inhaled ciclesonide is efficacious and well tolerated in the treatment of severe equine asthma in a large prospective European clinical trial.. Equine Vet J 2021 Nov;53(6):1094-1104.
- Bond SL, Greco-Otto P, MacLeod J, Galezowski A, Bayly W, Léguillette R. Efficacy of dexamethasone, salbutamol, and reduced respirable particulate concentration on aerobic capacity in horses with smoke-induced mild asthma.. J Vet Intern Med 2020 Mar;34(2):979-985.
- Bond SL, Workentine M, Hundt J, Gilkerson JR, Léguillette R. Effects of nebulized dexamethasone on the respiratory microbiota and mycobiota and relative equine herpesvirus-1, 2, 4, 5 in an equine model of asthma.. J Vet Intern Med 2020 Jan;34(1):307-321.
- Bond SL, Hundt J, Léguillette R. Effect of injected dexamethasone on relative cytokine mRNA expression in bronchoalveolar lavage fluid in horses with mild asthma.. BMC Vet Res 2019 Nov 6;15(1):397.
- Lavoie JP, Bullone M, Rodrigues N, Germim P, Albrecht B, von Salis-Soglio M. Effect of different doses of inhaled ciclesonide on lung function, clinical signs related to airflow limitation and serum cortisol levels in horses with experimentally induced mild to severe airway obstruction.. Equine Vet J 2019 Nov;51(6):779-786.
- Bond S, Léguillette R, Richard EA, Couetil L, Lavoie JP, Martin JG, Pirie RS. Equine asthma: Integrative biologic relevance of a recently proposed nomenclature.. J Vet Intern Med 2018 Nov;32(6):2088-2098.
- Lavoie JP, Leclere M, Rodrigues N, Lemos KR, Bourzac C, Lefebvre-Lavoie J, Beauchamp G, Albrecht B. Efficacy of inhaled budesonide for the treatment of severe equine asthma.. Equine Vet J 2019 May;51(3):401-407.
- Husulak ML, Manning ST, Meachem MD, Burgess HJ, Epp TY, Montgomery JB. Does antimicrobial therapy improve outcomes in horses with severe equine asthma and a positive tracheal wash bacterial culture?. Can J Vet Res 2018 Jul;82(3):184-191.
- Bond SL, Timsit E, Workentine M, Alexander T, Léguillette R. Upper and lower respiratory tract microbiota in horses: bacterial communities associated with health and mild asthma (inflammatory airway disease) and effects of dexamethasone.. BMC Microbiol 2017 Aug 23;17(1):184.
- Barton AK, Gehlen H. Pulmonary Remodeling in Equine Asthma: What Do We Know about Mediators of Inflammation in the Horse?. Mediators Inflamm 2016;2016:5693205.
- Murcia RY, Vargas A, Lavoie JP. The Interleukin-17 Induced Activation and Increased Survival of Equine Neutrophils Is Insensitive to Glucocorticoids.. PLoS One 2016;11(5):e0154755.
- Hirsch G, Lavoie-Lamoureux A, Beauchamp G, Lavoie JP. Neutrophils are not less sensitive than other blood leukocytes to the genomic effects of glucocorticoids.. PLoS One 2012;7(9):e44606.
- Fugazzola M, Barton AK, Niedorf F, Kietzmann M, Ohnesorge B. Non-genomic action of beclomethasone dipropionate on bronchoconstriction caused by leukotriene C4 in precision cut lung slices in the horse.. BMC Vet Res 2012 Sep 10;8:160.
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