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Co-inhalation of roflumilast, rather than formoterol, with fluticasone more effectively improves asthma in asthmatic mice.
Exp Biol Med (Maywood) 2017; 242(5):516-526EB

Abstract

Roflumilast is approved as an add-on therapy for chronic obstructive pulmonary disease. The inflammation in chronic obstructive pulmonary disease is mainly neutrophilic, while in asthma it is mainly eosinophilic, studies addressing role of roflumilast in eosinophilic inflammation are recommended. Also in severe asthma, the dominant inflammatory cells are neutrophils. Thus, roflumilast has a potential off-label use in the treatment of asthma. This study was designed to evaluate the effects of co-inhalation of roflumilast and fluticasone compared to that of formoterol and fluticasone in ovalbumin-sensitized and-challenged BALB/c mice. Besides normal control group, the ovalbumin-asthmatic mice were randomly divided into seven groups (n = 8): positive control, vehicle-treated, and five drug-treated groups. Treatments (µg/kg) were given as 15 min-inhalation once/day for five days as follows: roflumilast (500), formoterol (50), fluticasone (1000), roflumilast + fluticasone (500 + 1000), and formoterol + fluticasone (50 + 1000). Penh values were measured in conscious unrestrained mice using the single-chamber whole-body plethysmography. Airway hyperreactivity to inhaled methacholine was evaluated. Bronchoalveolar lavage fluid was used for the measurements of levels of IL-4, IL-5, TNF-α, OVA-specific IgE, and total and differential white cells. Lung sections were stained with hematoxylin and eosin and periodic acid-Schiff. The asthmatic mice showed significant increases in airway hyperreactivity which were significantly reversed by the combination treatments. The asthmatic mice showed significant increases in levels of IL-4, IL-5, TNF-α, ovalbumin-specific IgE, and total and differential white cells in bronchoalveolar lavage fluid. All treatments (except formoterol) significantly reversed these changes mainly with roflumilast + fluticasone. The asthmatic mice showed severe inflammatory infiltration and goblet cell hyperplasia which were maximally reversed by roflumilast + fluticasone, while minimally reversed by formoterol. In conclusion, co-inhalation of roflumilast + fluticasone more significantly improved inflammation and histopathological changes than co-inhalation of formoterol + fluticasone in ovalumin-asthmatic mice. Further studies are needed to help confirm the potential off-label add-on use of roflumilast in typical and atypical asthma and asthma-chronic obstructive pulmonary disease overlap syndrome. Impact statement Roflumilast, a selective phosphodiesterase-4 inhibitor, was approved for the treatment of chronic obstructive pulmonary disease (COPD). This study showed that co-inhalation of roflumilast and fluticasone significantly decreased airway hyperresponsiveness in ovalumin-asthmatic mice. Also, it more significantly improved inflammation and histopathological changes than co-inhalation of formoterol and fluticasone. The current results showed that inhaled roflumilast reduced counts of eosinophils, neutrophils, and macrophages in bronchoalveolar lavage fluid. Consequently, inhaled roflumilast might be of potential off-label benefit in treatment of eosinophilic and neutrophilic asthma and asthma-COPD overlap syndrome (ACOS). These results could also support other experimental and clinical studies addressing the same issue.

Authors+Show Affiliations

1 Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia. 2 Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo 11562, Egypt.3 Department of Pediatrics, Faculty of Medicine, KAU, Jeddah 21589, Saudi Arabia.1 Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University (KAU), Jeddah 21589, Saudi Arabia.4 Department of Pharmacology, Faculty of Medicine, KAU, Jeddah 21589, Saudi Arabia.5 Department of Pathology, Faculty of Medicine, Rabigh, KAU, Jeddah 21589, Saudi Arabia.5 Department of Pathology, Faculty of Medicine, Rabigh, KAU, Jeddah 21589, Saudi Arabia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28056550

Citation

Murad, Hussam A., et al. "Co-inhalation of Roflumilast, Rather Than Formoterol, With Fluticasone More Effectively Improves Asthma in Asthmatic Mice." Experimental Biology and Medicine (Maywood, N.J.), vol. 242, no. 5, 2017, pp. 516-526.
Murad HA, Habib HS, Rafeeq MM, et al. Co-inhalation of roflumilast, rather than formoterol, with fluticasone more effectively improves asthma in asthmatic mice. Exp Biol Med (Maywood). 2017;242(5):516-526.
Murad, H. A., Habib, H. S., Rafeeq, M. M., Sulaiman, M. I., Abdulrahman, A. S., & Khabaz, M. N. (2017). Co-inhalation of roflumilast, rather than formoterol, with fluticasone more effectively improves asthma in asthmatic mice. Experimental Biology and Medicine (Maywood, N.J.), 242(5), pp. 516-526. doi:10.1177/1535370216685006.
Murad HA, et al. Co-inhalation of Roflumilast, Rather Than Formoterol, With Fluticasone More Effectively Improves Asthma in Asthmatic Mice. Exp Biol Med (Maywood). 2017;242(5):516-526. PubMed PMID: 28056550.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Co-inhalation of roflumilast, rather than formoterol, with fluticasone more effectively improves asthma in asthmatic mice. AU - Murad,Hussam A, AU - Habib,Hamed S, AU - Rafeeq,Misbahuddin M, AU - Sulaiman,Mansour I, AU - Abdulrahman,Amer S, AU - Khabaz,Mohamad Nidal, Y1 - 2017/01/05/ PY - 2017/1/7/pubmed PY - 2017/6/15/medline PY - 2017/1/7/entrez KW - Asthma KW - fluticasone KW - formoterol KW - mice KW - off-label KW - ovalbumin KW - roflumilast SP - 516 EP - 526 JF - Experimental biology and medicine (Maywood, N.J.) JO - Exp. Biol. Med. (Maywood) VL - 242 IS - 5 N2 - Roflumilast is approved as an add-on therapy for chronic obstructive pulmonary disease. The inflammation in chronic obstructive pulmonary disease is mainly neutrophilic, while in asthma it is mainly eosinophilic, studies addressing role of roflumilast in eosinophilic inflammation are recommended. Also in severe asthma, the dominant inflammatory cells are neutrophils. Thus, roflumilast has a potential off-label use in the treatment of asthma. This study was designed to evaluate the effects of co-inhalation of roflumilast and fluticasone compared to that of formoterol and fluticasone in ovalbumin-sensitized and-challenged BALB/c mice. Besides normal control group, the ovalbumin-asthmatic mice were randomly divided into seven groups (n = 8): positive control, vehicle-treated, and five drug-treated groups. Treatments (µg/kg) were given as 15 min-inhalation once/day for five days as follows: roflumilast (500), formoterol (50), fluticasone (1000), roflumilast + fluticasone (500 + 1000), and formoterol + fluticasone (50 + 1000). Penh values were measured in conscious unrestrained mice using the single-chamber whole-body plethysmography. Airway hyperreactivity to inhaled methacholine was evaluated. Bronchoalveolar lavage fluid was used for the measurements of levels of IL-4, IL-5, TNF-α, OVA-specific IgE, and total and differential white cells. Lung sections were stained with hematoxylin and eosin and periodic acid-Schiff. The asthmatic mice showed significant increases in airway hyperreactivity which were significantly reversed by the combination treatments. The asthmatic mice showed significant increases in levels of IL-4, IL-5, TNF-α, ovalbumin-specific IgE, and total and differential white cells in bronchoalveolar lavage fluid. All treatments (except formoterol) significantly reversed these changes mainly with roflumilast + fluticasone. The asthmatic mice showed severe inflammatory infiltration and goblet cell hyperplasia which were maximally reversed by roflumilast + fluticasone, while minimally reversed by formoterol. In conclusion, co-inhalation of roflumilast + fluticasone more significantly improved inflammation and histopathological changes than co-inhalation of formoterol + fluticasone in ovalumin-asthmatic mice. Further studies are needed to help confirm the potential off-label add-on use of roflumilast in typical and atypical asthma and asthma-chronic obstructive pulmonary disease overlap syndrome. Impact statement Roflumilast, a selective phosphodiesterase-4 inhibitor, was approved for the treatment of chronic obstructive pulmonary disease (COPD). This study showed that co-inhalation of roflumilast and fluticasone significantly decreased airway hyperresponsiveness in ovalumin-asthmatic mice. Also, it more significantly improved inflammation and histopathological changes than co-inhalation of formoterol and fluticasone. The current results showed that inhaled roflumilast reduced counts of eosinophils, neutrophils, and macrophages in bronchoalveolar lavage fluid. Consequently, inhaled roflumilast might be of potential off-label benefit in treatment of eosinophilic and neutrophilic asthma and asthma-COPD overlap syndrome (ACOS). These results could also support other experimental and clinical studies addressing the same issue. SN - 1535-3699 UR - https://www.unboundmedicine.com/medline/citation/28056550/Co_inhalation_of_roflumilast_rather_than_formoterol_with_fluticasone_more_effectively_improves_asthma_in_asthmatic_mice_ L2 - http://journals.sagepub.com/doi/full/10.1177/1535370216685006?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -