Phosphodiesterase-4 Inhibitor Therapy for Lung Diseases

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).