Can Phosphodiesterase 4 Inhibitor Therapy Be Used in Respiratory Diseases Other Than Chronic Obstructive Pulmonary Disease?

Abstract

Selective phosphodiesterase 4 (PDE4) inhibitors have been extensively studied for the treatment of various respiratory diseases due to their broad anti-inflammatory and/or bronchodilator effects. Roflumilast, an oral selective PDE4 inhibitor, is currently used as a second-line treatment in patients with chronic obstructive pulmonary disease (COPD) with chronic bronchitis. Despite its proven efficacy in other respiratory disorders, including asthma, no other PDE4 inhibitor is approved for respiratory pathologies. This systematic review summarizes the therapeutic action of PDE4 inhibitors, their limitations, recent therapeutic success, and future targets for their use in respiratory diseases other than COPD. An electronic literature search was conducted on four databases, namely, PubMed, PubMed Central, Google Scholar, and ScienceDirect, to collect data on related studies done in humans and published in the English language in the last five years. After extensive analysis and quality appraisal, 11 studies were eligible and thus included in this review, consisting of two randomized controlled trials (RCT), one systematic review and meta-analysis, and eight literature reviews. Roflumilast is not approved for the treatment of asthma due to associated adverse effects and comparable efficacy to inhaled corticosteroids, which are considered the mainstay of asthma maintenance therapy. Hence, the importance of balancing the efficacy with minimizing the side effects is highlighted. Tanimilast (CHF6001), an inhalational selective PDE4 inhibitor, and ensifentrine, a combined PDE3/4 inhibitor, demonstrate the recent therapeutic success in asthma and warrant further large-scale clinical studies. Future researchers will focus on the specific endotype than the phenotype in asthma as a meaningful therapeutic approach due to the high heterogeneity noted in asthma. Current evidence suggests the possibility of PDE4 inhibitors as a novel therapeutic option for chronic cough, allergic rhinitis, and cystic fibrosis. Further evidence from new studies is eagerly anticipated to better understand the efficacy and safety of PDE4 inhibitors in these respiratory diseases.

PDE4 inhibitors: potential protective effects in inflammation and vascular diseases

“…PDE4D is highest in bladder and muscle tissues, followed by thyroid, heart, kidneys, lungs, and stomach ( Lakics et al, 2010 ). Understanding the distribution of PDE4 in the human body is essential for identifying potential targets of PDE4 inhibitors in different diseases ( Goonathilake et al, 2022 ).…”

Modulation of Human Dendritic Cell Functions by Phosphodiesterase-4 Inhibitors: Potential Relevance for the Treatment of Respiratory Diseases

“…For an extensive review on PDE4 inhibitors development, usage, role and side effects in therapy, which goes beyond the scope of this review, we refer the reader to the recent and comprehensive literature (e.g., [ 4 , 7 , 14 , 15 , 17 , 18 , 19 , 20 , 21 ]).…”

“…Apremilast is currently under clinical evaluation as a therapy to mitigate the severe inflammatory reactions associated with COVID-19 pneumonia (https://classic.clinicaltrials.gov/ct2/show/NCT04590586, accessed on 1 July 2023). Additionally, a number of molecules are currently under clinical trial for the treatment of respiratory diseases, as recently reviewed in several works [4,7,[14][15][16] and briefly summarized in Table 1.…”

“…For an extensive review on PDE4 inhibitors development, usage, role and side effects in therapy, which goes beyond the scope of this review, we refer the reader to the recent and comprehensive literature (e.g., [4,7,14,15,[17][18][19][20][21]). Dendritic cells are a heterogeneous group of cells originating in the bone marrow from both myeloid and lymphoid precursors.…”