The
phosphodiesterase (PDE) 4 is the predominant
cyclic AMP degrading
enzyme in a variety of inflammatory cells including eosinophils, neutrophils, macrophages, T cells and monocytes. In addition, this
enzyme is expressed in non-immune cells such as keratinocytes and fibroblasts. Highly selective
PDE4 inhibitors are currently under evaluation for the treatment of
asthma and/or
chronic obstructive pulmonary disease. Due to the broad anti-inflammatory/immuno-modulatory action of
PDE4 inhibitors, it has been proposed that
PDE4 inhibitors might also be efficacious for skin disorders such as
atopic dermatitis. Consequently,
PDE4 inhibitors including
cilomilast and
AWD 12-281 have been tested in several models of allergic and
irritant skin
inflammation. These
PDE4 inhibitors displayed strong anti-inflammatory action in models of
allergic contact dermatitis in mice, in the
arachidonic acid induced skin
inflammation in mice and in
ovalbumin sensitised guinea pigs. The determination of
cytokines in skin homogenates revealed that both Th1 as well as Th2
cytokines are suppressed by
PDE4 inhibitors, indicating an anti-inflammatory activity in both the Th2 dominated acute phase as well as the Th1 dominated chronic phase of
atopic dermatitis. Due to the suppression of Th1
cytokines, activity can also be expected in
psoriasis. Results of early clinical trials with both topically (
cipamfylline, CP80,633) and systemically (CC-10004) active
PDE4 inhibitors demonstrated efficacy in
atopic dermatitis and in the case of
CC-10004, also in
psoriasis.
AWD 12-281 (GW 842470) is currently under clinical evaluation for the topical treatment of
atopic dermatitis. Results concerning clinical efficacy of this potent and selective
PDE4 inhibitor are anxiously awaited.