Biology Reference
In-Depth Information
Rheumatoid arthritis is amenable to anti-TNF
a
monoclonal antibodies, which
highlights an important role this cytokine plays in disease pathology. Similarly,
T cells (e.g., Th1, Th17), macrophages, chondrocytes, and osteoblasts all play a role
in this disease (Nestle et al.
2009
). All these cell types express PDE4 and inhibition
of this enzyme can lead to a reduction in cell activity that might be conducive to a
beneficial action in this disease (Table
1
).
Preclinical studies have shown that PDE4 inhibitors can suppress pannus-like
inflammation in animals injected with methylated bovine serum albumin. Further-
more, PDE4 inhibitors suppressed cytokine production from peritoneal macro-
phages and inhibited synovial fibroblast proliferation in culture (Kobayashi et al.
2007
). The recent finding that PDE4 inhibitors suppressed IL-17 production from
human peripheral blood mononuclear cells and CD4+ T lymphocytes and inhibited
proliferation of human memory Th17 (Ma et al.
2008
) could explain the preclinical
findings. Indeed, the expression of IL-23 from human peripheral blood mono-
nuclear cells, a cytokine which supports the expansion of Th17 cells was suppressed
by PDE4 inhibition (Schafer et al.
2010
). Similarly, roflumilast partially attenuated
nitric oxide release from human chondrocytes in culture, these cells are involved in
articular cartilage destruction in rheumatoid arthritis (Tenor et al.
2002
). Loss of
bone is also a feature of rheumatoid arthritis, and PDE3 and PDE4 inhibitors have
been shown to augment the ability of prostaglandin E2 to promote murine osteo-
clast differentiation in co-cultures of calvarial osteoclasts and bone marrow cells
(Noh et al.
2009
). However, it is well established that PGE2 promotes bone for-
mation in vivo, and this anabolic effect is also observed with PDE4 inhibitors in
ovariectomized rats (Yao et al.
2007
). PDE4 inhibitors appear to suppress inflam-
mation, cartilage destruction, and bone loss in rheumatoid arthritis, but it remains
to be established whether this drug class will be significantly better than current
biological agents.
6 Unwanted Side Effects
Nausea and other gastrointestinal side effects are commonly reported side effects
associated with many PDE4 inhibitors and the mechanism responsible for these side
effects has been investigated in an attempt to discover nonemetic PDE4 inhibitors.
The direct recording of neuronal activity within the area postrema of dogs conclu-
sively demonstrated that substances known to cause nausea (e.g., apomorphine)
caused the excitation of neurons within this anatomical location (Carpenter et al.
1988
). Neuronal activity within the area postrema was also increased following the
systemic administration of 8-bromo cAMP or following elevation of endogenous
levels of cAMP within neurones by forskolin, an activator of adenylyl cyclase
(Carpenter et al.
1988
). Elevated levels of cAMP within the area postrema enhanced
the emetogenic response. Dogs treated with theophylline and the PDE4 selective
inhibitor, 4-(3-Butoxy-4-methoxyphenyl)methyl-2-imidazolidone (Ro 20-1724)
