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3.3 Other PDE4 Inhibitor/Nuclear Hormone
Receptor Combinations
In the above sections, the potential for combining PDE4 inhibitors with a glucocor-
ticoid or, indeed, a LABA/glucocorticoid combination was considered. However, it
is clear that many NHRs, including the progesterone receptor (PR), androgen
receptor (AR), and estrogen receptor may, in the presence of their cognate ligands,
repress proinflammatory transcriptional responses and proinflammatory gene
expression (Kalkhoven et al. 1996 ; McKay and Cidlowski 1999 ). Likewise, many
of the more recently characterized NHRs including the liver X receptor, peroxisome
proliferator-activated receptors (PPARs), and the various retinoic acid receptors
(RARs and RXRs) are also capable of downregulating proinflammatory genes and
are, consequently, being considered as alternative therapeutic options to glucocor-
ticoids (Farrow 2008 ). However, in addition to identifying novel anti-inflammatory
molecules, these advances also provide a trove of opportunity to develop novel
NHR-based combination therapies for the treatment of inflammatory diseases
(Ogawa et al. 2005 ). For example, like the GR, transcriptional activity of each
of the PR, the mineralocorticoid receptor (MR), the RAR a , and the AR have
previously been shown to be enhanced by elevated cAMP (Beck et al. 1992 ;
Gaillard et al. 2006 ; Kim et al. 2005 ; Massaad et al. 1999 ; Sartorius et al. 1993 ).
Moreover, there is evidence that agonists of PPAR g may show enhanced ability to
repress proinflammatory gene expression when combined with a LABA (Nie et al.
2005a ). Consequently, the idea that PDE4 inhibitors may be paired with activators
of NHRs other than GR is logical. Currently, it is unclear how widespread such
effects would be and caution is merited. Indeed, LXR-mediated transcription is
inhibited by activation of the cAMP/PKA cascade (Yamamoto et al. 2007b ).
Nevertheless, the PDE4 inhibitor, piclamilast (RP 73401), enhances transcriptional
activation by RAR a and it seems very likely that the inhibition of PDE4 may
provide a mechanism by which the ability of many NHR ligands can, therapeuti-
cally, be augmented (Parrella et al. 2004 ). Certainly, this provides impetus for
analyzing potential beneficial interactions between PDE4 inhibitors and activators
of NHRs.
4 Concluding Remarks
PDE4 inhibitors have been in clinical development for many years and it is,
perhaps, gratifying that the benzamide, roflumilast, which is being developed
jointly by Nycomed (formerly Altana) in Europe and Forest Research Institute in
the USA, was recently approved by the European Medicines Agency Committee
for Medicinal Products for Human Use ( http:/www.ema.europa.eu/pdfs/human/
opinion/Daxas_15986110en.pdf ) for the “ maintenance treatment of severe chronic
obstructive pulmonary disease associated with chronic bronchitis in adult patients
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