Harnessing the Clinical Efficacy of Phosphodiesterase 4 Inhibitors in Inflammatory Lung Diseases: Dual-Selective Phosphodiesterase Inhibitors and Novel Combination Therapies

  • Mark A. GiembyczEmail author
  • Robert Newton
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 204)


Phosphodiesterase (PDE) 4 inhibitors have been in development as a novel anti-inflammatory therapy for more than 20 years, with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, only one selective PDE4 inhibitor, roflumilast (Daxas ® ), has been approved for use in humans and available in Canada and the European Union in 2011 for the treatment of a specific population of patients with severe COPD. In many other cases, the development of PDE4 inhibitors of various structural classes has been discontinued due to lack of efficacy and/or dose-limiting adverse events. Indeed, for many of these compounds, it is likely that the maximum tolerated dose is either subtherapeutic or at the very bottom of the efficacy dose–response curve. Thus, a significant ongoing challenge that faces the pharmaceutical industry is to synthesize compounds with therapeutic ratios that are superior to roflumilast. Several strategies are being considered, but clinically effective compounds with an optimal pharmacophore have not, thus far, been reported. In this chapter, alternative means of harnessing the clinical efficacy of PDE4 inhibitors are described. These concepts are based on the assumption that additive or synergistic anti-inflammatory effects can be produced with inhibitors that target either two or more PDE families or with a PDE4 inhibitor in combination with other anti-inflammatory drugs such as a glucocorticoid.


Airway inflammation Asthma cAMP Chronic obstructive pulmonary disease Combination therapies Gene transactivation Glucocorticoids Long-acting β2-adrenoceptor agonists Nuclear hormone receptors Phosphodiesterase 4 



Airway hyperresponsiveness


Activator protein


Androgen receptor


Blood pressure


Central nervous system


Chronic obstructive pulmonary disease


Forced expiratory volume in 1 s


Glucocorticoid-induced leucine zipper


Glucocorticoid receptor


Glucocorticoid response element


Histone deacetylase


Hypoxic pulmonary vasoconstriction


Heart rate


Inhaled corticosteroid




Long-acting β2-adrenoceptor agonist


Left ventricular pressure


Mitogen-activated protein kinase phosphatase


Mineralocorticoid receptor


Nuclear factor-kappaB




Pulmonary hypertension




cAMP-dependent protein kinase


Pulmonary artery pressure


Progesterone receptor


Pulmonary vascular resistance


Retinoic acid receptors


Short-acting β2-adrenoceptor agonist



RN is a Canadian Institutes of Health Research (CIHR) New Investigator and an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Scholar. Work in the laboratories of RN and MAG is supported by CIHR operating grants (MOP 68828 and MOP 93742, respectively) and educational research grants from AstraZeneca, Gilead Sciences, GlaxoSmithKline, and Nycomed.


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© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Airways Inflammation Research Group, Departments of Physiology and Pharmacology, Institute of Infection, Immunity and InflammationUniversity of CalgaryCalgaryCanada
  2. 2.Cell Biology and Anatomy, Institute of Infection, Immunity and InflammationUniversity of CalgaryCalgaryCanada

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