Biology Reference
In-Depth Information
5 Other Inflammatory Diseases and PDE4
Numerous inflammatory conditions such as psoriasis (Nestle et al.
2009
),
rheumatoid arthritis (Taylor and Feldmann
2009
), and inflammatory bowel disease
(Abraham and Cho
2009
) are characterized by a complex interplay between cells
resulting in their activation and recruitment, release of proinflammatory cytokines,
and tissue damage. Biologicals directed against cytokines are one of the most
important therapies to emerge in the past decade and have revolutionized the
treatment of inflammatory diseases as exemplified by those targeting TNF
a
(Nestle
et al.
2009
; Taylor and Feldmann
2009
; Abraham and Cho
2009
). It is therefore of
interest that PDE4 inhibitors can suppress TNF
a
production by various inflamma-
tory cell types, and inhibit the activity of immune cells so critical in these diseases
(Table
1
). It is therefore no surprise that PDE4 inhibitors are also being considered
for the treatment of a number of nonrespiratory inflammatory diseases.
Earlier observations suggested the targeting of cAMP PDE might prove benefi-
cial in the treatment of skin inflammatory disease. For example, potential deficits in
adenylyl cyclase signaling in psoriasis (Wright et al.
1973
) and expression of a
novel monocyte-derived cAMP PDE in atopic dermatitis (Chan et al.
1993
) were
reported. Consequently, several selective PDE4 inhibitors have been evaluated in
clinical trials. Patients with psoriasis and treated with apremilast, an orally active
PDE4 inhibitor demonstrated an improvement in clinical scores and reduced T-cell
number in the dermis in an open-label clinical trial (Gottlieb et al.
2008
). Similarly,
the systemic administration of apremilast reduced pathological features of psoriatic
human skin transplanted onto immunocompromised mice (Schafer et al.
2010
). One
of the advantages of inflammatory dermatoses is that topical administration could
limit the systemic liability associated with orally administered PDE4 inhibitors and
this strategy has been adopted for the development of AN2728 for the treatment of
psoriasis and atopic dermatitis with promising results in phase II clinical trials
(Nazarian and Weinberg
2009
; Akama et al.
2009
).
Inflammatory bowel diseases might also be amenable to treatment with PDE4
inhibitors since Th1 and Th17 cells are implicated in this disease and the activity
of these cell types can be suppressed by PDE4 inhibitors (Table
1
). The PDE4
inhibitor, tetomilast, appeared to reduce various indices of inflammation in IL10-
deficient mice that spontaneously develop chronic gastrointestinal inflammation
characterized by mucus secretion, rectal prolapse, and diarrhea (Ichikawa et al.
2008
). Tetomilast has also been evaluated in a phase II clinical trial in active
ulcerative colitis (Schreiber et al.
2007
). Improvement in disease as defined by a
disease activity index of
3 was achieved in 53% (25 mg dose) and 39% (50 mg
dose) of patients after 8 weeks of treatment, although this was not statistically
different from the placebo group. However, post-hoc analysis revealed that patients
with more severe disease showed significant improvement when treated with
tetomilast. One of the potential issues with this study is the reporting of nausea
and emesis, particularly with the higher dose of tetomilast which will be of concern
when treating patients with gastrointestinal inflammation.
