AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 188 2013
Bianca Beghe` 1, Klaus F. Rabe2,3, and Leonardo M. Fabbri1
1Section of Respiratory Diseases, Department of Oncology, Haematology, and Respiratory Diseases, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy; 2Department of Pulmonology, Christian Albrechts University Kiel, member of the German Center for Lung Research (DZL), Kiel, Germany; and 3LungenClinic Grosshansdorf, member of the DZL, Grosshansdorf, Germany
Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the breakdown of cAMP and/or cyclic guanosine mono- phosphate (GMP) to their inactive form. PDE4 is the main selective cAMP-metabolizing enzyme in inflammatory and immune cells. Because PDE4 is highly expressed in leukocytes and other inflamma- tory cells involved in the pathogenesis of inflammatory lung dis- eases, such as asthma and chronic obstructive pulmonary disease (COPD), inhibition of PDE4 has been predicted to have an anti- inflammatory effect and thus therapeutic efficacy. The limited and inconsistent efficacy and side effects of the early compounds made their further development less desirable in asthma, given the excellent efficacy/tolerability ratio of inhaled steroids. The lack of effective antiinflammatory drug treatment for COPD has thus shifted the interest in development toward COPD. Roflumilast, the only PDE4 inhibitor that has reached the market because of the good efficacy/tolerability ratio, is recommended for patients with COPD with severe airflow limitation, symptoms of chronic bronchitis, and a history of exacerbations, whose disease is not adequately con- trolled by long-acting bronchodilators. Albeit safe, it maintains significant side effects (diarrhea, nausea, weight loss) that make it intolerable in some patients. Future developments of PDE4 inhib- itors include extended indications of roflumilast (1) in patients with COPD, and (2) in other respiratory (e.g., asthma) and nonrespiratory chronic inflammatory/metabolic conditions (e.g., diabetes), as well as (3) the development of new molecules with PDE4 inhibitory prop- erties with an improved efficacy/tolerability profile.
Keywords: asthma; emphysema; inflammation; smoking; chronic bron- chitis
Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the breakdown of the second messengers cAMP and/ or cyclic guanosine monophosphate (GMP) to their inactive forms (1–3).
PDE4 is the main selective cAMP-metabolizing enzyme in inflammatory and immune cells (1, 4). Increases in intracellular cAMP by inhibition of cAMP-degrading PDE4 enzymes reduce most proinflammatory functions of these cells.
Because PDE4 is highly expressed in leukocytes and other inflammatory cells involved in the pathogenesis of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), inhibition of PDE4 has been predicted to have an antiinflammatory effect and thus therapeutic efficacy. In the early 1990s, the focus for the use of PDE4 inhibitors was on asthma. However, the limited and inconsistent efficacy and side effects of the early compounds made their further development less desirable in asthma, given the widespread use of inhaled cor- ticosteroids (ICS) as a safe and effective alternative. Indeed, the lack of effective antiinflammatory drug treatment for COPD has shifted the interest in development toward COPD in recent years (1, 5).
In the first generation of selective PDE4 inhibitors, cilomilast was shown to have antiinflammatory properties and some clinical efficacy, including improvement of lung function and prevention of exacerbations in patients with COPD (6). However, its use was limited by inconsistent efficacy and significant side effects, particularly gastrointestinal. The only PDE4 inhibitor so far that has demonstrated clinical efficacy with limited and tolera- ble side effects is roflumilast. Roflumilast is therefore the only representative of this new class of drugs that has gained mar- keting approval globally so far (5, 7).
MECHANISMS OF ACTION
Roflumilast has been shown in vitro to decrease the release of inflammatory mediators from neutrophils, the expression of ad- hesion molecules on T lymphocytes, and the release of cyto- kines such as IL-1b or tumor necrosis factor (TNF)-a from a variety of cell types (8). In vivo, roflumilast reduces cytokine release from a range of inflammatory cells, including neutro- phils, eosinophils, and T lymphocytes (2, 9).
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