an2728 and apremilast

Atopic dermatitis (AD) is a highly prevalent, chronic inflammatory skin disease that affects children and adults. The pathophysiology of AD is complex and involves skin barrier and immune dysfunction. Many immune cytokine pathways are amplified in AD, including T helper (Th) 2, Th22, Th17 and Th1. Current treatment guidelines recommend topical medications as initial therapy; however, until recently, only two drug classes were available: topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). Several limitations are associated with these agents. TCSs can cause a wide range of adverse effects, including skin atrophy, telangiectasia, rosacea and acne. TCIs can cause burning and stinging, and the prescribing information lists a boxed warning for a theoretical risk of malignancy. Novel medications with new mechanisms of action are necessary to provide better long-term control of AD. Phosphodiesterase 4 (PDE4) regulates cyclic adenosine monophosphate in cells and has been shown to be involved in the pathophysiology of AD, making it an attractive therapeutic target. Several PDE4 inhibitors are in clinical development for use in the treatment of AD, including crisaborole, which recently became the first topical PDE4 inhibitor approved for treatment of mild to moderate AD. This review will further describe the pathophysiology of AD, explain the possible role of PDE4 in AD and review PDE4 inhibitors currently approved or being investigated for use in AD.

Topics: Acetamides; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclic Nucleotide Phosphodiesterases, Type 4; Cytokines; Dermatitis, Atopic; Drug Approval; Humans; Immune System; Inflammation; Phosphodiesterase Inhibitors; Phthalic Acids; Pyridines; Quinazolines; Risk; Skin; Thalidomide

Phosphodiesterase inhibitors are commonly used drugs. Specific phosphodiesterase inhibitors with anti-inflammatory properties are being assessed as dermatological treatments.. To describe important aspects of phosphodiesterase inhibition and the safety and efficacy of 2 phosphodiesterase- 4 inhibitors being studied for the treatment of dermatologic diseases. We did a non-systematic analysis of literature on phosphodiesterase inhibition followed by a review of published information on apremilast and topical AN2728 and their use for psoriasis and atopic dermatitis.. Apremilast and topical AN2728 have modest efficacy in treatment of psoriasis. Apremilast achieved PASI-75 scores ranging from 24-33%. In phase 2 studies, AN2728 had modest efficacy for psoriasis (40% of patients achieved a ≥ 2 grade improvement as assessed by the Overall target Plaque Severity Score). In phase 2 studies of AN2728 use in atopic dermatitis, subjects achieved a 71% improvement from baseline Atopic Dermatitis Severity Index. In all studies, most adverse effects were minimal. The limitations of this paper are the limited number of published studies, the lack of long-term data, and the lack of head -to - head trials directly comparing phosphodiesterase inhibitors with other treatments.. Phosphodiesterase inhibitors constitute a widely used class of drugs that may see growing use for inflammatory dermatologic diseases.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclic AMP; Dermatitis, Atopic; Humans; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Psoriasis; Thalidomide; Tissue Distribution

Topics: Aminopyridines; Benzamides; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Cyclic AMP; Cyclopropanes; Down-Regulation; Humans; Inflammation Mediators; Interleukin-18; Interleukin-1alpha; Interleukin-8; Keratinocytes; MAP Kinase Signaling System; Phosphodiesterase 4 Inhibitors; Psoriasis; Thalidomide; Tumor Necrosis Factor-alpha

The treatment of atopic dermatitis in adults is based on the use of topical steroids and emollients. When AD is resistant to a well-conducted topical treatment, phototherapy or systemic treatments can be used: ciclosporin, methotrexate, azathioprine or mycophenolate mofetil. The therapeutic landscape of adult AD is about to change and even be revolutionized by the imminent arrival of new treatments: topical phosphodiesterase 4 inhibitors, topical or systemic JAK inhibitors, anti-IL-4 and/or antiIL-13 biotherapies (dupilumab, tralokinumab, lebrikizumab), anti-IL-31 (nemolizumab), anti-TSLP.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclosporine; Dermatitis, Atopic; Dermatologic Agents; Glucocorticoids; Humans; Methotrexate; Mycophenolic Acid; Piperidines; Pyrimidines; Pyrroles; Thalidomide; Ustekinumab