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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
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 204)

Abstract

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.

Keywords

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

Abbreviations

AHR

Airway hyperresponsiveness

AP

Activator protein

AR

Androgen receptor

BP

Blood pressure

CNS

Central nervous system

COPD

Chronic obstructive pulmonary disease

FEV1

Forced expiratory volume in 1 s

GILZ

Glucocorticoid-induced leucine zipper

GR

Glucocorticoid receptor

GRE

Glucocorticoid response element

HDAC

Histone deacetylase

HPV

Hypoxic pulmonary vasoconstriction

HR

Heart rate

ICS

Inhaled corticosteroid

IL

Interleukin

LABA

Long-acting β2-adrenoceptor agonist

LVP

Left ventricular pressure

MKP

Mitogen-activated protein kinase phosphatase

MR

Mineralocorticoid receptor

NFκB

Nuclear factor-kappaB

PDE

Phosphodiesterase

PH

Pulmonary hypertension

PHA

Phytohemagglutinin

PKA

cAMP-dependent protein kinase

Ppa

Pulmonary artery pressure

PR

Progesterone receptor

PVR

Pulmonary vascular resistance

RAR/RXR

Retinoic acid receptors

SABA

Short-acting β2-adrenoceptor agonist

Notes

Acknowledgments

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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