- Samirao A, Berry TM, Goreshi R, Simpson EL. A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol 2012;148(8):890–7.
- Li H, Zuo J, Tang W. Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front Pharmacol 2018;9:1048.
- Konrad FM, Bury A, Schick MA, et al. The unrecognized effects of phosphodiesterase 4 on epithelial cells in pulmonary inflammation. PLoS ONE 2015;10(4):e0121725.
- Peter D, Jin SL, Conti M, et al. Differential expression and function of phosphodiesterase 4 (PDE4) subtypes in human primary CD4+ T cells: predominant role of PDE4D. J Immunol 2007;178(8):4820–31.
- Schafer PH, Truzzi F, Parton A, et al. Phosphodiesterase 4 in inflammatory diseases: Effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex. Cell Signal 2016;28(7):753–63.
- Conteras S, Milara J, Morcillo E, Cortijo J. Selective Inhibition of Phosphodiesterases 4A, B, C and D Isoforms in Chronic Respiratory Diseases: Current and Future Evidences. Curr Pharm Des 2017;23(14):2073–83.
Background
What do we already know about this topic?
- Phosphodiesterase (PDE) is a class of enzymes that catalyse the hydrolysis of cyclic nucleotides.
- PDE4 plays a central role in modulating signal transduction by cAMP messenger inside a variety of different immune cells.1,2
- PDE4 inhibition is associated with downregulation of inflammatory cytokines (TNFα, IFNγ, IL-5, IL-13, IL-17A, IL-23) and upregulation of anti-inflammatory IL-10.1,2
- Four subtypes (A–D) have been identified; B and D are the most important in inflammation.3-6
- Orismilast is a next-generation PDE4 inhibitor developed to potently inhibit subtypes B and D.
- It is currently in clinical trials for inflammatory disorders, including psoriasis, atopic dermatitis, and hidradenitis suppurativa.
- The formulation has been changed from immediate- to modified release to improve gastrointestinal tolerability.
How was this study conducted?
- Inhibition of PDE enzymes with orismilast and PDE4 subtypes with orismilast and apremilast were measured using IMAP technology and radiometric assay, respectively.
- Inhibition of lipopolysaccharide-induced TNFα release was measured in human peripheral blood mononuclear cells (PBMC).
- Inhibition of anti-CD3/CD28-induced TNFα release was measured in human whole blood.
- Efficacy of oral orismilast (0.1, 0.3, 1 and 10 mg/kg) and oral dexamethasone 2 mg/kg was investigated in the oxazolone mouse model of chronic inflammation.
