• Tuberculosis and Respiratory Diseases
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• v.85 no.1
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• pp.67-73
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• 2022

Background: Bronchiectasis patients with neutrophilic airway inflammation develop symptoms of chronic cough, sputum production, and recurrent exacerbations. Roflumilast has anti-inflammatory actions via decreased neutrophilic airway inflammation. The effectiveness of roflumilast to reduce bronchiectasis exacerbation has never been evaluated. Methods: We conducted a double-blinded, randomized, placebo-controlled trial. Our primary objective was to assess the effect of roflumilast compared with that of a placebo in reducing exacerbation rates in bronchiectasis patients. The secondary objectives were the changes in forced expiratory volume in 1 second (FEV₁) and St. George's Respiratory Questionnaire (SGRQ). Bronchiectasis patients older than 18 years who had had two exacerbations during the previous 12 months were randomly assigned to receive either 500 ㎍ of either roflumilast or a placebo once daily for 6 months in a 1:1 ratio. Results: Forty bronchiectasis patients who had experienced exacerbations were screened. Thirty patients completed the study after 6 months of treatment: roflumilast group (n=15) and placebo group (n=15). The rates of exacerbations were 0.57 and 0.59 per patient in the roflumilast and placebo groups, respectively. Prebronchodilator FEV₁ increased by 0.07 L from baseline in the roflumilast group and decreased by 0.015 L in the placebo group, but the difference was not significant. No significant differences were observed in the change of SGRQ scores between the roflumilast and placebo groups. Roflumilast had significant side effects, including loss of appetite and headache. Conclusion: Roflumilast did not significantly affect the rate of exacerbations or quality of life. However, FEV₁ tended to improve more in the roflumilast group than in the placebo group.

• Tuberculosis and Respiratory Diseases
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• v.81 no.4
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• pp.299-304
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• 2018

Background: Roflumilast is the only approved oral phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease (COPD) in patients with chronic bronchitis and a history of frequent exacerbations. The purpose of this study was to examine the incidence of adverse effects associated with roflumilast treatment in a real-world setting. Further, we compared the incidence of adverse effects and the discontinuation rate among patients receiving different doses. Methods: We identified all outpatients diagnosed with COPD at Seoul St. Mary's Hospital between May 2011 and September 2016 and retrospectively reviewed their medical records. Roflumilast was prescribed to patients in doses of $500{\mu}g$ and $250{\mu}g$. Results: A total of 269 COPD patients were prescribed roflumilast in our hospital during the study period. Among them, 178 patients were treated with $500{\mu}g$ and 91 patients were treated with $250{\mu}g$. The incidence of adverse effects was 38.2% in the $500{\mu}g$ group and 25.3% in the $250{\mu}g$ group (p=0.034). The discontinuation rate of roflumilast was 41.6% (n=74) in the $500{\mu}g$ group and 23.1% (n=21) in the $250{\mu}g$ group (p=0.003). When adjusted by age, sex, smoking status, and lung function, $500{\mu}g$ dose was significantly associated with the discontinuation of roflumilast (odds ratio, 2.87; p<0.001). Conclusion: There was a lower incidence of adverse effects and discontinuation among patients treated with $250{\mu}g$ compared with $500{\mu}g$ dose. Further studies regarding the optimal dose of roflumilast are required.

• Mass Spectrometry Letters
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• v.6 no.2
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• pp.38-42
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• 2015

Roflumilast analogs are a group of drugs which act as selective photodiesterase (PDE-4) inhibitor for the treatment severe chronic pulmonary disease associated with chronic brochnonities. Structural identification of degradation products using high resolution mass spectrometry and theoretical investigation by density functional theory have been successfully carried out on roflumilast to identify four degradation products namely, 3,5-dichloropyridin-4-amine, N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-hydroxy benzamide, N-(3,5-dichloropyridin-4-yl)-3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzamide and 3-(cyclopropylmethoxy)-N-(3,5-dichloro-1-oxidopyridin-4-yl)-4-(difluoro methoxy) benzamide, generated in alkali, acidic and oxidative conditions.

• Tuberculosis and Respiratory Diseases
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• v.81 no.2
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• pp.138-147
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• 2018

Background: Recent studies show that mitophagy, the autophagy-dependent turnover of mitochondria, mediates pulmonary epithelial cell death in response to cigarette smoke extract (CSE) exposure and contributes to the development of emphysema in vivo during chronic cigarette smoke (CS) exposure, although the underlying mechanisms remain unclear. Methods: In this study, we investigated the role of mitophagy in the regulation of CSE-exposed lung bronchial epithelial cell (Beas-2B) death. We also investigated the role of a phosphodiesterase 4 inhibitor, roflumilast, in CSE-induced mitophagy-dependent cell death. Results: Our results demonstrated that CSE induces mitophagy in Beas-2B cells through mitochondrial dysfunction and increased the expression levels of the mitophagy regulator protein, PTEN-induced putative kinase-1 (PINK1), and the mitochondrial fission protein, dynamin-1-like protein (DRP1). CSE-induced epithelial cell death was significantly increased in Beas-2B cells exposed to CSE but was decreased by small interfering RNA-dependent knockdown of DRP1. Treatment with roflumilast in Beas-2B cells inhibited CSE-induced mitochondrial dysfunction and mitophagy by inhibiting the expression of phospho-DRP1 and -PINK1. Roflumilast protected against cell death and increased cell viability, as determined by the lactate dehydrogenase release test and the MTT assay, respectively, in Beas-2B cells exposed to CSE. Conclusion: These findings suggest that roflumilast plays a protective role in CS-induced mitophagy-dependent cell death.

• Tuberculosis and Respiratory Diseases
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• v.78 no.4
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• pp.321-325
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• 2015

Background: The adverse effects of the phosphodiesterase-4 inhibitor roflumilast, appear to be more frequent in clinical practice than what was observed in chronic obstructive pulmonary disease (COPD) clinical trials. Thus, we designed this study to determine whether adverse effects could be reduced by starting roflumilast at half the dose, and then increasing a few weeks later to $500{\mu}g$ daily. Methods: We retrospectively investigated 85 patients with COPD who had taken either $500{\mu}g$ roflumilast, or a starting dose of $250{\mu}g$ and then increased to $500{\mu}g$. We analyzed all adverse events and assessed differences between patients who continued taking the drug after dose escalation and those who had stopped. Results: Adverse events were reported by 22 of the 85 patients (25.9%). The most common adverse event was diarrhea (10.6%). Of the 52 patients who had increased from a starting dose of $250{\mu}g$ roflumilast to $500{\mu}g$, 43 (82.7%) successfully maintained the $500{\mu}g$ roflumilast dose. No difference in factors likely to affect the risk of adverse effects, was detected between the dose-escalated and the discontinued groups. Of the 26 patients who started with the $500{\mu}g$ roflumilast regimen, seven (26.9%) discontinued because of adverse effects. There was no statistically significant difference in discontinuation rate between the dose-escalated and the control groups (p=0.22). Conclusion: Escalating the roflumilast dose may reduce treatment-related adverse effects and improve tolerance to the full dose. This study suggests that the dose-escalated regimen reduced the rate of discontinuation. However, longer-term and larger-scale studies are needed to support the full benefit of a dose escalation strategy.

• The Journal of Korean Medicine
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• v.34 no.2
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• pp.10-19
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• 2013

Objectives: In the present study, we evaluate the anti-inflammatory effect of Lonicerae Flos on cigarette-induced lung inflammatory responses in animal model of chronic obstructive pulmonary diseases (COPD). Methods: To inspect the effects of Lonicerae Flos, we evaluated Lonicerae Flos functions in vivo including immune cell profiles in bronchoalveolar lavage (BAL) fluid, cytokine production and tissue morphological changes. Results: Lonicerae Flos significantly inhibited immune cell infiltrations into the BAL fluid (neutrophils, macrophages, lymphocytes). TNF-${\alpha}$, and interleukin-6 (IL-6) were substantially decreased in the BAL fluid of Lonicerae Flos-treated mice compared with cigarette-exposed control mice. In addition, the hypertrophy of goblet cells in the epithelial cells was reduced in both Lonicerae Flos- and roflumilast-treated mice. Conclusions: The results of this study provide evidence that treatment with Lonicerae Flos exerts strong therapeutic effects against cigarette-induced lung inflammation in vivo. Therefore, this herbal medicine may represent a novel therapeutic agent for lung inflammation in general, as well as a specific agent for the treatment of COPD.