- Efficacy and safety profile of roflumilast in a real-world experience. [Journal Article]
- JTJ Thorac Dis 2019; 11(4):1100-1105
- CONCLUSIONS: Roflumilast reduced exacerbations and hospitalizations in our real-world population with severe COPD. AEs are common and frequently leading to discontinuation of roflumilast therapy.
- Optimizing Drug Therapies in Patients with COPD in the US Nursing Home Setting. [Review]
- DADrugs Aging 2019 Jun 07
- Chronic obstructive pulmonary disease (COPD) can be a disabling disease, and the impact on older adults is particularly evident in the nursing home setting. Chronic obstructive pulmonary disease is p…
Chronic obstructive pulmonary disease (COPD) can be a disabling disease, and the impact on older adults is particularly evident in the nursing home setting. Chronic obstructive pulmonary disease is present in about 20% of nursing home residents, most often in women, and accounts for significant healthcare utilization including acute care visits for exacerbations and pneumonia, as well as worsening heart disease and diabetes mellitus. The emphasis on hospital readmissions is particularly important in nursing homes where institutions have quality measures that have financial implications. Optimizing drug therapies in individuals with COPD involves choosing medications that not only improve symptoms, but also decrease the risk of exacerbations. Optimizing the treatment of comorbidities such as heart disease, infections, and diabetes that may affect COPD outcomes is also an important consideration. Depending on the nursing home setting and the patient, the options for optimizing COPD drug therapies may be limited owing to patient-related factors such as cognition and physical impairment or available resources, primarily reimbursement-related issues. Choosing the best drug therapy for COPD in older adults is limited by the difficulty in assessing respiratory symptoms using standardized assessment tools and potentially decreased inspiratory ability of frail individuals. Because of cognitive and physical impediments, ensuring optimal delivery of inhaled medications into the lungs has significant challenges. Long-acting bronchodilators, inhaled corticosteroids, and roflumilast decrease the risk of exacerbations, although inhaled corticosteroids should be used judiciously in this population because of the risk of pneumonia and oropharyngeal side effects. Treatment of COPD exacerbations should occur early and consideration should be made to the benefits and risks of systemic corticosteroids and antibiotics. Clinical research in the COPD population in nursing homes is clearly lacking, and ripe for discovery of effective management strategies.
- PDE4 Inhibition as a therapeutic target for alcoholic liver disease: from bedside to bench. [Journal Article]
- HepHepatology 2019 May 13
- CONCLUSIONS: Increased PDE4 plays a pathogenic role in the development of ALD. Hence, directed interventions aimed at inhibiting PDE4 might be an effective treatment for ALD. This article is protected by copyright. All rights reserved.
- A Way to Increase the Bioaccesibility and Photostability of Roflumilast, a COPD Treatment, by Cyclodextrin Monomers. [Journal Article]
- PPolymers (Basel) 2019 May 04; 11(5)
- Roflumilast is an orally available inhibitor of phosphodiesterase (PDE) type 4, which is widely used in chronic obstructive pulmonary diseases. However, it has low solubility and adverse effects incl…
Roflumilast is an orally available inhibitor of phosphodiesterase (PDE) type 4, which is widely used in chronic obstructive pulmonary diseases. However, it has low solubility and adverse effects include diarrhea and nausea. Since its solubilization may improve treatment and, dismissing any adverse effects, its interaction with cyclodextrins (CDs) was studied. The Higuchi-Connors method was used to determine the complexation constant with different CDs, pH values and temperatures. Molecular docking was used to predict interaction between the complexes. An in vitro digestion experiment was carried out to test roflumilast protection. Finally, the photostability of the complex was evaluated. The complex formed with β-CD had the highest K11 value (646 ± 34 M-1), although this value decreased with increasing temperature. Similarly, K11 decreased as the pH increased. In vitro digestion showed that CDs protect the drug during digestion and even improve its bioaccessibility. Finally, CDs reduced the drug's extreme photosensitivity, originating a fluorescence signal, which is described for first time. The kinetic parameters of the reaction were obtained. This study not only completes the complexation study of roflumilast-CD, but also points to the need to protect roflumilast from light, suggesting that tablets containing the drug might be reformulated.
- Impact of Phosphodiesterase 4 Inhibition on the Operational Efficacy, Response Maxima, and Kinetics of Indacaterol-Induced Gene Expression Changes in BEAS-2B Airway Epithelial Cells: A Global Transcriptomic Analysis. [Journal Article]
- MPMol Pharmacol 2019; 96(1):56-72
- The effects of phosphodiesterase (PDE) 4 inhibitors on gene expression changes in BEAS-2B human airway epithelial cells are reported and discussed in relation to the mechanism(s) of action of roflumi…
The effects of phosphodiesterase (PDE) 4 inhibitors on gene expression changes in BEAS-2B human airway epithelial cells are reported and discussed in relation to the mechanism(s) of action of roflumilast in chronic obstructive pulmonary disease (COPD). Microarray-based gene expression profiling failed to identify mRNA transcripts that were differentially regulated by the PDE4 inhibitor 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) after 1, 2, 6, or 18 hours of exposure. However, real-time polymerase chain reaction analysis revealed that GSK 256066 was a weak stimulus, and the negative microarray results reflected low statistical power due to small sample sizes. Furthermore, GSK 256066, roflumilast, and its biologically active metabolite roflumilast N-oxide generally potentiated gene expression changes produced by the long-acting β 2-adrenoceptor agonists (LABAs) salmeterol, indacaterol, and formoterol. Many of these genes encode proteins with antiviral, anti-inflammatory, and antibacterial activities that could contribute to the clinical efficacy of roflumilast in COPD. RNA-sequencing experiments established that the sensitivity of genes to salmeterol varied by ∼7.5-fold. Consequently, the degree to which a PDE4 inhibitor potentiated the effect of a given concentration of LABA was gene-dependent. Operational model fitting of concentration-response curve data from cells subjected to fractional, β 2-adrenoceptor inactivation determined that PDE4 inhibition increased the potency and doubled the efficacy of LABAs. Thus, adding roflumilast to standard triple therapy, as COPD guidelines recommend, may have clinical relevance, especially in target tissues where LABAs behave as partial agonists. Collectively, these results suggest that the genomic impact of roflumilast, including its ability to augment LABA-induced gene expression changes, may contribute to its therapeutic activity in COPD.
- Phosphodiesterase-4 Inhibitor Roflumilast Attenuates Pulmonary Air Emboli-Induced Lung Injury. [Journal Article]
- JSJ Surg Res 2019; 241:24-30
- CONCLUSIONS: PAE-induced ALI presents with lung inflammation with neutrophilic sequestration, pulmonary edema, hyperpermeability, increased cytokine levels, and activation of the NF-κB pathway. Roflumilast attenuates lung edema and inflammation and downregulates the NF-κB pathway and cytokines.
- Mucociliary Clearance in Former Tobacco Smokers with Both Chronic Obstructive Pulmonary Disease and Chronic Bronchitis and the Effect of Roflumilast. [Journal Article]
- JAJ Aerosol Med Pulm Drug Deliv 2019 Apr 08
- CONCLUSIONS: Measurements of MCC30, MCC60, and MCC90 are repeatable and reliable in former tobacco smokers with both COPD and CB. One month of treatment with roflumilast did not improve MCC in this limited study. Airway narrowing in the larger, central airways of these subjects could lead to decreased FEV1, increased inner region deposition of the radiolabeled particles, and the associated increase in symptoms of dyspnea, cough, and sputum.
- Pharmacological and molecular dynamics analyses of differences in inhibitor binding to human and nematode PDE4: Implications for management of parasitic nematodes. [Journal Article]
- PlosPLoS One 2019; 14(3):e0214554
- Novel chemical controls are needed that selectively target human, animal, and plant parasitic nematodes with reduced adverse effects on the host or the environment. We hypothesize that the phosphodie…
Novel chemical controls are needed that selectively target human, animal, and plant parasitic nematodes with reduced adverse effects on the host or the environment. We hypothesize that the phosphodiesterase (PDE) enzyme family represents a potential target for development of novel nematicides and anthelmintics. To test this, we identified six PDE families present in the nematode phylum that are orthologous to six of the eleven human PDE families. We characterized the binding interactions of family-selective PDE inhibitors with human and C. elegans PDE4 in conjunction with molecular dynamics (MD) simulations to evaluate differences in binding interactions of these inhibitors within the PDE4 catalytic domain. We observed that roflumilast (human PDE4-selective inhibitor) and zardaverine (selective for human PDE3 and PDE4) were 159- and 77-fold less potent, respectively, in inhibiting C. elegans PDE4. The pan-specific PDE inhibitor isobutyl methyl xanthine (IBMX) had similar affinity for nematode and human PDE4. Of 32 residues within 5 Å of the ligand binding site, five revealed significant differences in non-bonded interaction energies (van der Waals and electrostatic interaction energies) that could account for the differential binding affinities of roflumilast and zardaverine. One site (Phe506 in the human PDE4D3 amino acid sequence corresponding to Tyr253 in C. elegans PDE4) is predicted to alter the binding conformation of roflumilast and zardaverine (but not IBMX) into a less energetically favorable state for the nematode enzyme. The pharmacological differences in sensitivity to PDE4 inhibitors in conjunction with differences in the amino acids comprising the inhibitor binding sites of human and C. elegans PDE4 catalytic domains together support the feasibility of designing the next generation of anthelmintics/nematicides that could selectively bind to nematode PDEs.
- Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/TLR4 inflammatory and fibrogenic pathways. [Journal Article]
- LSLife Sci 2019 Apr 01; 222:245-254
- CONCLUSIONS: Our study manifested the up-regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP-mediated TLR4 inflammatory and fibrogenic signaling pathways.
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- Influence of roflumilast on sepsis mice through the JAK/STAT signaling pathway. [Journal Article]
- EREur Rev Med Pharmacol Sci 2019; 23(3):1335-1341
- CONCLUSIONS: Roflumilast can improve lung tissue morphology of sepsis mice by inhibiting the JAK/STAT signaling pathway.