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Phosphodiesterase type IV inhibitors
General information
Phosphodiesterase type IV is a major regulator of cyclic adenosine monophosphate metabolism in many cell types, including smooth muscle, proinflammatory calls, and immune cells [ ]. Inhibitors of phosphodiesterase type IV, such as apremilast, cilomilast, and roflumilast, inhibit the synthesis of tumor necrosis factor alpha in monocytes, monocyte-derived derived dendritic cells, and macrophages and inhibit CD4 + T cell proliferation and production of cytokines (e.g. interleukin 2 and interleukin 4), leukotriene B4 synthesis, and the formation of reactive oxygen species [ ]. In early preclinical and clinical studies inhibition of phosphodiesterase type IV resulted in bronchodilatation, neuromodulation, and reduced numbers and activation of inflammatory cells relevant to obstructive lung disease [ ].
Cilomilast is completely absorbed and has a life–life of about 6 hours. Roflumilast has a longer half, allowing once-daily dosing.
Uses
Because of disappointing results in clinical trials, the development of cilomilast was terminated before marketing. Roflumilast is used to treat chronic obstructive pulmonary disease. Apremilast is used to treat psoriasis and has also been studied in ankylosing spondylitis and Behçet's syndrome.
General adverse effects and adverse reactions
The trials of roflumilast suggest an NNT B of 5 to prevent one exacerbation; however, such benefits have to be weighed against the significant adverse reactions, although it has been argued that the adverse events that have led to withdrawal were transient and occurred early on in treatment. Weight loss in the 6-month trial was of similar magnitude to that in the 1-year trial suggesting that this is an early phenomenon. However, this adverse reaction is of concern, especially in COPD, in which a low BMI is associated with a worse prognosis. On the other hand, this adverse reaction has been suggested to be of some benefit and has been associated with a possible reduction in both blood glucose and glycosylated haemoglobin [ ]. Whether roflumilast is more efficacious than inhaled glucocorticoids in preventing exacerbations has yet to be determined, but currently clinicians have to weigh the adverse reactions profile against the increased apparent risk of pneumonia with inhaled glucocorticoids [ ].
Drug studies
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