an2728 and Dermatitis--Atopic

New topical agents have been developed for the treatment of atopic dermatitis (AD) in recent years. This systematic review is intended to synthesize the clinical trial literature and concisely report the updated safety and adverse effects of topical medications used to treat atopic dermatitis in children.. A systematic search of Cochrane Library, Embase, PubMed and ClinicalTrials.gov from inception to March 2022 was conducted for trials of topical medications used to treat AD in patients <18 years (PROSPERO #CRD42022315355). Included records were limited to English-language publications and studies of ≥3 weeks duration. Phase 1 studies and those that lacked separate paediatric safety reporting were excluded.. A total of 5005 records were screened; 75 records met inclusion criteria with 15 845 paediatric patients treated with tacrolimus, 12 851 treated with pimecrolimus, 3539 with topical corticosteroid (TCS), 700 with crisaborole and 202 with delgocitinib. Safety data was well reported in tacrolimus trials with the most frequently reported adverse events being burning sensation, pruritus and cutaneous infections. Two longitudinal cohort studies were included, one for tacrolimus and one for pimecrolimus, which found no significant increased risk of malignancy with topical calcineurin inhibitor (TCI) use in children. Skin atrophy was identified as an adverse event in TCS trials, which other medications did not. Systemic adverse events for the medications were largely common childhood ailments.. Data discussed here support the use of steroid-sparing medications (tacrolimus, pimecrolimus, crisaborole, delgocitinib) as safe options with minimal adverse events for managing paediatric AD, although a larger number of TCI studies reported burning and pruritus compared to TCS studies. TCS was the only medication class associated with reports of skin atrophy in this review. The tolerability of these adverse events should be considered when treating young children. This review was limited to English-language publications and the variable safety reporting of trial investigators. Many newer medications were not included due to pooled adult and paediatric safety data that did not meet inclusion criteria.

Topics: Adult; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Humans; Longitudinal Studies; Pruritus; Tacrolimus; Treatment Outcome

This is a comprehensive and current guide for the diagnosis, differential diagnosis, treatment, and management of eczematous dermatitis, with a focus on atopic dermatitis, irritant and allergic contact dermatitis, hand dermatitis including recurrent vesicular and hyperkeratotic types, asteatotic dermatitis, and nummular or discoid dermatitis. Diagnostic options highlighted are clinical history, physical examination, and patch testing. Therapeutic options highlighted are moisturizers, topical corticosteroids, topical calcineurin inhibitors, crisaborole, phototherapy, and systemic medications including biologics.

Topics: Administration, Topical; Adrenal Cortex Hormones; Aged; Biological Products; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Allergic Contact; Dermatitis, Atopic; Diagnosis, Differential; Eczema; Humans; Infant; Middle Aged; Patch Tests; Phototherapy; Quality of Life

Approval of the new topical phosphodiesterase 4 inhibitor crisaborole ointment, 2%, to treat mild-to-moderate atopic dermatitis (AD) warrants careful consideration of available efficacy and safety data for topical therapies to contribute to a better understanding of the role of crisaborole in the treatment of mild-to-moderate AD. A literature review was conducted to identify results of randomized, blinded, vehicle-controlled trials of topical agents for the treatment of AD published from January 1, 1997 to April 30, 2018. This review summarizes the efficacy and safety data of topical therapies including corticosteroids, calcineurin inhibitors, and crisaborole and it shows that comparison among available agents is difficult because of differing methodologies used across clinical trials and that there is considerable variability in safety reporting among AD trials. Published clinical studies for crisaborole demonstrate its efficacy and manageable safety profile.\ \ J Drugs Dermatol. 2020;19(1):50-64. doi:10.36849/JDD.2020.4508

Topics: Administration, Cutaneous; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Glucocorticoids; Humans; Phosphodiesterase 4 Inhibitors; Randomized Controlled Trials as Topic; Severity of Illness Index

The prevalence of atopic dermatitis (AD) in geriatric populations of industrialized countries is currently estimated at 3-4% and continues to increase. AD is associated with significant morbidity, increased susceptibility to infection, and symptoms of pruritus and pain. Treatments may negatively affect elderly patients; thus, plans should be optimized for this population.. This review summarizes treatment options for AD in the elderly. A systematic review of the literature was conducted using the key terms atopic dermatitis, elderly, geriatric, systemic therapy, therapy, and topical therapy in PubMed. Searches yielded articles on skincare management and topical and systemic pharmacotherapies.. Proper use of moisturizer is crucial in all patients with AD. Topical corticosteroids are commonly prescribed; however, they carry an increased risk of adverse events such as skin atrophy. Systemic corticosteroids should be avoided in elderly patients due to questionable efficacy and increased adverse events. Topical calcineurin inhibitors and crisaborole are similarly efficacious with an excellent safety profile. Cyclosporine, azathioprine, methotrexate, and mycophenolate mofetil are systemic agents available for the treatment of refractory AD; however, insufficient data exist to indicate the superiority of any one agent. Dupilumab is a safe and efficacious injectable therapy in elderly patients.

Topics: Aged; Antibodies, Monoclonal, Humanized; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Cyclosporine; Dermatitis, Atopic; Dermatologic Agents; Humans; Pain; Pruritus; Treatment Outcome

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). This post hoc, pooled analysis identified demographic characteristics associated with early response to crisaborole.. Early response was defined as day 8 Investigator’s Static Global Assessment (ISGA) success (clear [0] or almost clear [1] with ≥2-grade improvement), ISGA clear/almost clear, or Severity of Pruritus Scale (SPS) response (≥1-point improvement). Correlations between early response and day-29 response were calculated.. Patients were more likely to be early ISGA success responders if they were aged <12 years (P=0.0023), were white (P=0.0316), had moderate baseline disease by ISGA (P=0.0003), had not received prior AD treatment (P=0.0213), had disease duration shorter than or equal to the median (≤6.45 years; P=0.0349), or did not concurrently use antihistamines (P=0.0148). Similar early response results were observed for patients achieving ISGA clear or almost clear; however, they were more likely to have mild baseline disease by ISGA (P<0.0001) or mild percentage of treatable body surface area involvement (5 to <16; P<0.0001). Patients aged <12 years (P=0.0001) or with moderate baseline disease (P=0.0475) were more likely to be early responders based on SPS criteria. By all 3 definitions, patients who achieved early response at day 8 were more likely to be responders at day 29 (P<0.0001).. Based on this analysis, patients aged <12 years were more likely to be early responders to crisaborole per all 3 definitions. Early response to crisaborole was a predictor of response at day 29.. ClinicalTrials.gov, NCT02118766 and NCT02118792 J Drugs Dermatol. 2020;19(6): doi:10.36849/JDD.2020.5095THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Topics: Administration, Cutaneous; Adolescent; Age Factors; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Demography; Dermatitis, Atopic; Female; Humans; Male; Ointments; Phosphodiesterase 4 Inhibitors; Randomized Controlled Trials as Topic; Treatment Outcome; United Kingdom; United States

Mild to moderate atopic dermatitis (AD) occurs frequently in children and adults and is usually managed through the use of pharmacologic treatments, such as topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs), and good skin care practices. As chronic TCS or TCI can lead to the development of adverse effects, there is a need for safe, alternative treatments for patients with resistant AD. A systemic literature review was performed to examine the safety and efficacy of topical agents currently in phase II and phase III clinical trials for AD. Our team searched the databases, PubMed, Google Scholar, and ClinicalTrials.gov, on March 2020 for studies pertaining to the use of topical agents in AD. Key words included each drug (tapinarof, crisaborole, ARQ-151 cream, ruxolitinib) or "topical agents"; combined with "atopic dermatitis"; Articles published within the last 5 years were included as references. References within retrieved articles were also reviewed to identify potentially missed studies. A total of 24 articles were included in this review. Tapinarof, crisaborole, and ruxolitinib lead to statistically significant improvements in multiple disease severity scores. ARQ-151 cream achieved statistical significance in secondary endpoints, including vIGA-AD and EASI-75, but not in the primary endpoint of the study. All topical agents were well-tolerated by study participants. The findings demonstrate that tapinarof, crisaborole, ARQ-151 cream, and ruxolitinib are safe, effective treatment options for patients with mild to moderate AD. \ \ J Drugs Dermatol. 2020;19(10):956-959. doi: 10.36849/JDD.2020.5214.

Topics: Administration, Cutaneous; Aminopyridines; Benzamides; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cyclopropanes; Dermatitis, Atopic; Dermatologic Agents; Humans; Nitriles; Pyrazoles; Pyrimidines; Resorcinols; Severity of Illness Index; Skin Cream; Stilbenes; Treatment Outcome

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Drug Design; Eczema; Humans; Onychomycosis; Psoriasis; Skin Diseases; Treatment Outcome

A soft drug (SD) displays a metabolically labile spot and, after having exerted its activity in the site of action, undergoes a fast metabolism, leading to inactive metabolites. The SD approach has recently found widespread application in the dermatological field because it provides a means of localising the therapeutic effect in skin, while minimising systemic exposure. The literature is rapidly growing of successful examples of compounds targeting sphingosine-1-phosphate receptor 1 (S1PR1), transient receptor potential vanilloid 1 (TRPV1), Janus kinase (JAK), caspase 1, and histone deacetylase (HDAC), for the treatment of skin inflammatory, autoimmune, and oncological diseases. As a demonstration of the potential of this strategy, the SD approach recently led to the approval of crisaborole, a soft phosphodiesterase 4 (PDE4) inhibitor, for atopic dermatitis, while other agents are in clinical development.

Topics: Animals; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatologic Agents; Drug Development; Humans; Phosphodiesterase 4 Inhibitors; Skin Diseases

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

Herein we review recent developments in our understanding and treatment of atopic dermatitis. Key insights from the recent literature are summarized, from findings on the pathogenesis of this multifactorial disease to a new and more nuanced understanding of its natural history. Therapeutic advances and new data on comorbidities are also discussed.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Baths; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Comorbidity; Dermatitis, Atopic; Dermatologic Agents; Environmental Exposure; Humans; Janus Kinase Inhibitors; Pain; Patient Education as Topic; Peanut Hypersensitivity; Phosphodiesterase 4 Inhibitors; Sodium Hypochlorite

The evolving discoveries in atopic dermatitis (AD) shed light on disease pathogenesis and allow better management of patients. Dupiluamab was the first targeted agent approved for AD, proving for the first time AD can be treated with a single cytokine antagonism. Nevertheless, because not all patients respond to dupilumab and AD has a heterogeneous phenotype, more treatment options are much needed. This article reviews recent and exciting developments in AD, because ongoing or pipeline clinical trials for AD will ultimately expand and redefine a novel treatment paradigm for this common disease.

Topics: Administration, Cutaneous; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Cytokines; Dermatitis, Atopic; Dermatologic Agents; Emollients; Glucocorticoids; Humans; Janus Kinase Inhibitors; Microbiota; Phosphodiesterase 4 Inhibitors; T-Lymphocytes, Helper-Inducer; Th1 Cells; Th17 Cells; Th2 Cells; Ustekinumab

Topical medication is the central treatment for patients with atopic dermatitis (AD), but the options are limited. Phosphodiesterase 4 (PDE4) inhibitors are a new candidate for AD therapy.. To evaluate the efficacy and safety of topical PDE4 inhibitors in mild to moderate AD.. Clinical trials were identified from MEDLINE, Embase, Cochrane Controlled Register of Trials, Chinese medical databases (Wanfang, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, and China Science and Technology Journal Database), ClinicalTrials.gov, and other trial registries from inception to August 15, 2018. No restrictions on languages were placed.. Only double-blind randomized clinical trials with topical PDE4 inhibitors vs topical vehicle treatment for patients with mild to moderate AD were included.. Two reviewers independently extracted study features, intervention details, and outcomes. A meta-analysis was performed using the random-effects model. The Cochrane Collaboration's risk of bias assessment tool was used to assess the risk of bias. Funnel plots and Egger tests were used to assess the publication bias.. Changes from baseline in target lesion score were expressed in terms of standardized mean differences (SMDs) with 95% CIs. Outcomes of investigators' assessment and safety were expressed in terms of relative risk with 95% CIs.. Seven studies were identified, which included 1869 patients with mild to moderate AD. Overall, compared with the topical vehicle control, topical application of PDE4 inhibitors was associated with a significant decrease in target lesion score (SMD -0.40; 95% CI, -0.61 to -0.18; P < .001) and a higher response rate in investigators' assessment of clear or almost clear skin (relative risk, 1.50; 95% CI, 1.33-1.70; P < .001). There was no difference in treatment-related adverse events or in adverse events that required discontinuation of therapy. Subgroup analyses indicated that after 14 and 28 days of therapy with PDE4 inhibitors, target lesion score was significantly decreased. However, these beneficial effects were displayed only for the PDE4 inhibitors crisaborole and AN2898 (crisaborole at day 14: SMD, -0.59; 95% CI, -1.15 to -0.02; P = .04; AN2898 at day 14: SMD, -0.76; 95% CI, -1.38 to -0.13; P = .02; crisaborole at day 28: SMD, -0.86; 95% CI, -1.44 to -0.28; P = .004; AN2898 at day 28: SMD, -0.68; 95% CI, -1.30 to -0.05; P = .03). Heterogeneity was not significant across studies.. This meta-analysis suggests that topical PDE4 inhibitors are a safe and effective treatment for mild to moderate AD. Current evidence supports the use of crisaborole or AN2898 as the choice of maintenance or sequential therapy for mild to moderate AD.

Topics: Administration, Topical; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; China; Dermatitis, Atopic; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Patient Safety; Phosphodiesterase 4 Inhibitors; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Atopic dermatitis is a common cutaneous disease with significant morbidity affecting children and adults. The mainstay of atopic dermatitis therapy has typically included emollients, topical corticosteroids, and topical calcineurin inhibitors. Among the newer advances recently introduced is crisaborole (Eucrisa™), a phosphodiesterase type-4 inhibitor (PDE-4) for the treatment of mild moderate atopic dermatitis. Evidence from phase 3 trials demonstrates crisaborole as an efficacious topical agent with a favorable safety profile and limited systemic exposure. While the efficacy of crisaborole compared to existing therapies remains unknown, crisaborole is a promising candidate in the treatment of atopic dermatitis.

Topics: Administration, Cutaneous; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase III as Topic; Dermatitis, Atopic; Humans; Ointments; Phosphodiesterase 4 Inhibitors

Topics: Animals; Boron Compounds; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Drug Design; Humans; Multiple Myeloma; Onychomycosis

Atopic dermatitis (AD) is the most common inflammatory skin disease driven by both terminal keratinocyte differentiation defects and type 2 immune responses, and this condition causes psychological and social morbidity. Although patients with severe AD require systemic immunotherapy, conventional agents including ciclosporin could not be used for several years due to side effects such as nephrotoxicity, hypertension and long-term risks of malignancy. It is well known that dupilumab, which blocks receptor binding of both IL-4 and IL-13, is remarkably efficacious in the treatment of AD. We have entered a new era when many novel topical and systemic agents that may have great potential in AD treatment are emerging through clinical trials. The purpose of this article is to summarize the efficacy and safety of the current topical and systemic therapies in AD by reviewing recently published papers regarding phase II/III clinical trials. It is revealed that topical phosphodiesterase 4 inhibitors and Janus kinase (JAK) inhibitors are promising treatments for AD. Moreover, systemic therapies such as biologics targeting IL-13 and oral JAK inhibitors show strong efficacy in AD.

Topics: Acrylamides; Administration, Topical; Antibodies, Monoclonal, Humanized; Biological Products; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Humans; Immunotherapy; Interleukin-13; Janus Kinase Inhibitors; Molecular Targeted Therapy; Phosphodiesterase 4 Inhibitors; Piperidines; Pyridines; Pyrimidines; Pyrroles; Resorcinols; Stilbenes; TRPV Cation Channels

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. The number of people affected by AD is relatively high and seems to be rising. Although mild and moderate forms of the disease can be well controlled by the use of emollients, topical corticosteroids, and topical calcineurin inhibitors, treatment of severe is still a huge challenge. The new hope is biologic drugs, magic bullets in allergy, targeted at different points of the complex pathomechanism of inflammation in AD. In this review, novel biologic therapies are discussed, including recombinant monoclonal antibodies directed against various interleukin pathways (such as IL-4, IL-13, TSLP, IL-31, and IL-12/23), on immunoglobulin E, molecules acting as T cells, B cells, etc. Of biological drugs, the most promising seems to be anti-IL-4/IL-13 therapy (dupilumab-the biological agent) and phosphodiesterase-4 inhibitor (crisaborole-a small molecule). A deep understanding of the AD pathomechanism provides a new perspective for tailor-made treatment of severe atopic dermatitis.

Topics: Administration, Topical; Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Therapy; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Cytokines; Dermatitis, Atopic; Emollients; Humans; Male; Molecular Targeted Therapy; Signal Transduction; Skin

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, with a lifetime prevalence of up to 20% and substantial effects on quality of life. AD is characterized by intense itch, recurrent eczematous lesions and a fluctuating course. AD has a strong heritability component and is closely related to and commonly co-occurs with other atopic diseases (such as asthma and allergic rhinitis). Several pathophysiological mechanisms contribute to AD aetiology and clinical manifestations. Impairment of epidermal barrier function, for example, owing to deficiency in the structural protein filaggrin, can promote inflammation and T cell infiltration. The immune response in AD is skewed towards T helper 2 cell-mediated pathways and can in turn favour epidermal barrier disruption. Other contributing factors to AD onset include dysbiosis of the skin microbiota (in particular overgrowth of Staphylococcus aureus), systemic immune responses (including immunoglobulin E (IgE)-mediated sensitization) and neuroinflammation, which is involved in itch. Current treatments for AD include topical moisturizers and anti-inflammatory agents (such as corticosteroids, calcineurin inhibitors and cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) inhibitors), phototherapy and systemic immunosuppressants. Translational research has fostered the development of targeted small molecules and biologic therapies, especially for moderate-to-severe disease.

Topics: Administration, Topical; Adrenal Cortex Hormones; Azathioprine; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Chronic Disease; Dermatitis, Atopic; Filaggrin Proteins; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Intermediate Filament Proteins; Methotrexate; Phosphodiesterase 4 Inhibitors; Quality of Life; Severity of Illness Index; Urticaria

Atopic dermatitis (AD) is an extremely common condition affecting as many as 10-20% of children and 2-10% of adults. A particularly distressing symptom of AD is pruritus. One of the important aspects of AD is inflammation associated with increased activity of phosphodiesterase 4 (PDE4), resulting in decreased intracellular levels of cyclic adenosine monophosphate, which in turn causes increased production of inflammatory cytokines. Crisaborole was developed as a small-molecule, boron-based, selective PDE4 inhibitor that can be used topically. Clinical trials have demonstrated its efficacy in treating patients with mild to moderate AD, resulting in significant relief of pruritus. Unlike PDE4 inhibitors that act systemically, crisaborole does not cause significant gastrointestinal adverse effects. The most common adverse effect has been temporary stinging and burning in about 4% of patients upon application of the 2% ointment. To date there is no evidence of atrophy, telangiectasia or hypopigmentation resulting from its use. Crisaborole is the first topically applied PDE4 inhibitor to be approved by the FDA for use in AD.

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase II as Topic; Dermatitis, Atopic; Humans; Phosphodiesterase Inhibitors

Several immunologic mediators-phosphodiesterase (PDE), interleukin (IL), small molecules, and Janus kinase-have been implicated in the pathogenesis of atopic dermatitis, and evidence has shown that blocking these mediators can help modify the disease process. Several new topical medications have been developed that target the enzyme PDE; crisaborole was recently approved by the US Food and Drug Administration (FDA) for the treatment of atopic dermatitis, and phase II studies have been completed on OPA-15406. The phase III clinical trial results of the systemic medication dupilumab, an inhibitor of the IL-4 receptor α subunit (which inhibits both IL-4 and IL-13 signaling), are currently being reviewed by the FDA.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatologic Agents; Humans; Interleukin-4 Receptor alpha Subunit; Phosphodiesterase 4 Inhibitors

Phosphodiesterase 4 (PDE4) is a cyclic AMP degrading enzyme in leukocytes. Several decades ago, increased PDE activity was demonstrated in patients with atopic dermatitis (AD). Currently, several PDE4 inhibitors in both topical and oral formulation have been developed to target the inflammatory cascade of AD. This review shows the pathogenic rationale behind these inhibitors, and discusses multiple PDE4 inhibitors that are under evaluation or in the market. PDE4 inhibitors may be considered as favorable agents in the repertoire of current interventions for AD.

Topics: Anisoles; Anti-Inflammatory Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclic Nucleotide Phosphodiesterases, Type 4; Dermatitis, Atopic; Humans; Nitriles; Phosphodiesterase 4 Inhibitors; Phthalic Acids; Quinazolines

Crisaborole and dupilumab represent the first 2 Food and Drug Administration (FDA)-approved therapies for atopic dermatitis (AD) in more than 15 years, and there are many promising drugs currently in development. This new wave of therapeutics capitalizes on the large body of work clarifying the pathogenesis of AD over the last several decades. In particular, type 2 cytokine-driven inflammation and skin barrier dysfunction are key processes underlying AD pathogenesis.

Topics: Anisoles; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antipruritics; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatologic Agents; Emollients; Humans; Infant; Infant Formula; Interleukin-13; Interleukin-4; Nitriles; Phosphodiesterase 4 Inhibitors; Phthalic Acids; Probiotics; Quinazolines

Crisaborole ointment 2% (Eucrisa™) is a novel, anti-inflammatory inhibitor of phosphodiesterase 4 (PDE4) that is available in the USA for the topical treatment of mild to moderate atopic dermatitis in patients aged ≥ 2 years. In two short-term (28 days), identically designed, multicentre, phase III studies in this patient population, topical therapy with crisaborole ointment 2% reduced disease severity and pruritus severity compared with vehicle, with the effect established early and sustained over the course of treatment. Improvements in the other signs of atopic dermatitis (erythema, exudation, excoriation, induration/papulation, and lichenification) were also seen. Crisaborole ointment 2% was generally well tolerated in the short-term studies, with its favorable safety profile maintained over the longer term (up to 52 weeks) in a multicentre, extension study. Most treatment-emergent adverse events (TEAEs) were of mild to moderate severity and considered unrelated to the study medication. Moreover, the incidence of application-site pain following short- and longer-term topical therapy with crisaborole ointment 2% was low. In conclusion, crisaborole ointment 2% is an effective and generally well tolerated new topical option for the management of mild to moderate atopic dermatitis in patients aged ≥ 2 years, with the potential to effectively treat this patient population over the longer term without the safety concerns associated with other current topical anti-inflammatory agents.

Topics: Administration, Topical; Adult; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Humans; Ointments; Treatment Outcome

Crisaborole 2% topical ointment is an anti-inflammatory, non-steroidal phosphodiesterase 4 inhibitor which is currently under investigation for its potential role in the treatment of atopic dermatitis and psoriasis. Areas covered: So far, 7 trials have been completed in atopic dermatitis. The 2% strength appeared to be the superior dosing regimen. Pruritus improved significantly within one week. The improvements in objective efficacy assessments in crisaborole-treated patients were also statistically significant compared to the vehicle. Expert commentary: Crisaborole has several key features in its mode of action which distinguish it from existing treatments for atopic dermatitis (AD), notably its activity against the phosphodiesterase E4 (PDE4) pathway, regulating cyclic AMP (cAMP) levels. This is less immunosuppressive than other pathways and has no effect on skin thinning. The pathway interrupts the itch sensation (pruritus) which means that the itch-scratch cycle, the bane in the life of patients with AD, is interrupted, usually as early as a few days into treatment. Hence, with the promising safety profile demonstrated, early treatment of mild to moderate AD patients might help to control AD better and improve quality of life for patients.

Topics: Administration, Topical; Anti-Inflammatory Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclic Nucleotide Phosphodiesterases, Type 4; Dermatitis, Atopic; Disease Progression; Humans; Ointments; Phosphodiesterase Inhibitors; Treatment Outcome

Two post hoc analyses assessed the antipruritic activity of crisaborole topical ointment, 2% (crisaborole; Anacor Pharmaceuticals, Inc., Palo Alto, CA), a first-in-class boron-based phosphodiesterase-4 inhibitor in development for treatment of mild to moderate atopic dermatitis (AD).. Two pooled analyses included data from 4 studies evaluating crisaborole in AD (study 1, phase 1b, systemic exposure, safety, and pharmacokinetics [PK] under maximal-use conditions in children and adolescents; study 2, phase 2a, safety and PK in adolescents; study 3, phase 2a, efficacy and safety in adults; study 4, phase 2, efficacy and safety in adolescents). Pooled data from studies 1 and 2 included whole body assessments; studies 3 and 4 included target lesion assessments. Pruritus severity was evaluated using a 4-point rating scale (0=none to 3=severe). Efficacy assessments included percent change from baseline in pruritus severity scores at days 8 (first pooled assessment), 15, 22, and 29 (whole body assessments) or days 15 (first pooled assessment), 22, and 29 (target lesions). Paired t-tests comparing change from baseline against zero were used to calculate P values. Categorical shifts in pruritus severity were also assessed (no to mild pruritus, 0-1.5; moderate to severe pruritus, 2-3).. In the pooled analysis of studies 1 and 2 (N=57), the percent change from baseline in pruritus severity scores were 63.0% and 64.9% at days 8 and 29, respectively (P<0.001 for each). Similar results were observed in the pooled analysis of studies 3 and 4 (N=67). In both analyses, most patients had mild to no pruritus from the first time point assessed through the remainder of treatment.. Treatment with crisaborole topical ointment, 2% resulted in statistically significant reductions in pruritus severity at the first time point evaluated in both analyses. These findings provide preliminary evidence of the antipruritic activity of crisaborole topical ointment, 2%.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dermatitis, Atopic; Drug Compounding; Female; Humans; Male; Middle Aged; Ointments; Pruritus; Treatment Outcome; Young Adult

Crisaborole topical ointment, 2% (formerly known as AN2728) is a benzoxaborole, nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor investigational compound that recently completed phase 3 studies for the treatment of mild to moderate atopic dermatitis (AD). The unique configuration of boron within the crisaborole molecule enables selective targeting and inhibition of PDE4, an enzyme that converts the intracellular second messenger 3'5'-cyclic adenosine monophosphate (cAMP) into the active metabolite adenosine monophosphate (AMP). By inhibiting PDE4 and thus increasing levels of cAMP, crisaborole controls inflammation. The use of boron chemistry enabled synthesis of a low-molecular-weight compound (251 daltons), thereby facilitating effective penetration of crisaborole through human skin. In vitro experiments showed that crisaborole inhibits cytokine production from peripheral blood mononuclear cells in a pattern similar to other PDE4 inhibitors and distinct from corticosteroids. Crisaborole also displayed topical anti-inflammatory activity in a skin inflammation model. Once crisaborole reaches systemic circulation after topical application, it is metabolized to inactive metabolites. This limits systemic exposure to crisaborole and systemic PDE4 inhibition. In phase 1 and 2 clinical studies, crisaborole ointment, 2% was generally well tolerated and improved AD disease severity scores, pruritus, and all other AD signs and symptoms. Two large, randomized, controlled, phase 3, pivotal clinical trials assessing the efficacy and safety of crisaborole topical ointment, 2% in children, adolescents, and adults with mild to moderate AD were recently completed with positive results.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cytokines; Dermatitis, Atopic; Drug Evaluation, Preclinical; Humans; Ointments; Phosphodiesterase 4 Inhibitors; Treatment Outcome

Atopic dermatitis (AD), a chronic, relapsing, inflammatory skin disease that is characterized by intense pruritus and eczematous lesions with up to 90% of patients presenting with mild to moderate disease. Current topical treatments for AD have not changed in over 15 years and are associated with safety concerns. In AD, overactivity of phosphodiesterase 4 (PDE4), leads to inflammation and disease exacerbation. Crisaborole Topical Ointment, 2%, is a novel, nonsteroidal, topical anti-inflammatory PDE4 inhibitor currently being investigated for the treatment of mild to moderate AD. Preliminary studies in children and adults demonstrated favorable efficacy and safety profiles. Crisaborole may represent an anti-inflammatory option that safely minimizes the symptoms and severity of AD and that can be used for both acute and long-term management.

Topics: Administration, Topical; Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Ointments; Phosphodiesterase 4 Inhibitors

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

Cytokines are signaling molecules that are believed to be key factors in perpetuating the inflammatory process in psoriasis and atopic dermatitis. AN-2728, being developed by Anacor Pharmaceuticals Inc, is a topically administered, boron-containing, anti-inflammatory compound that inhibits PDE4 activity and thereby suppresses the release of TNFalpha, IL-12, IL-23 and other cytokines. At the time of publication, three phase Ib clinical trials, a IIa trial and a IIb trial of AN-2728 in patients with psoriasis had been completed; the compound was also undergoing phase II development for atopic dermatitis, but no data were available for this indication. AN-2728 was reported to be well tolerated and to demonstrate significant effects on markers of efficacy, with results that were comparable to positive controls. AN-2728 appears to have good therapeutic potential, although further and larger trials are required to assess the long-term safety and characterize the broad utility of this drug.

Topics: Animals; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cytokines; Dermatitis, Atopic; Humans; Inflammation; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Psoriasis

The aim of this study was to evaluate the clinical efficacy of crisaborole ointment in the treatment of vulvar leukoplakia.. A prospective, randomized controlled clinical trial was conducted, and a total of 100 patients with vulvar leukoplakia were divided into the observation group (n=50) treated with crisaborole ointment and the control group (n=50) treated with vitamin E. The symptom improvement and vulvar leukoplakia score after 2 weeks of treatment were analyzed, and the clinical efficacy of vulvar leukoplakia was evaluated by referring to the Guidelines for Clinical Research of New Drugs of Traditional Chinese Medicine (2018 Edition).. After 2 weeks of treatment, the overall score of lesions in the observation group decreased, and the total treatment efficiency of patients in the observation group was 92% (46/50), which was significantly higher than that of 52% (26/50) in the control group P<0.05).. Crisaborole ointment can effectively treat vulvar leukoplakia, improving the symptoms and pathological changes of the vulvar skin.

Topics: Dermatitis, Atopic; Double-Blind Method; Humans; Leukoplakia; Ointments; Prospective Studies; Treatment Outcome

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Humans; Ointments; Scleroderma, Localized; Treatment Outcome

Safe and effective long-term topical treatments for atopic dermatitis (AD) remain limited.. In this phase 2a, single-center, intrapatient, and vehicle-controlled study, we examine the mechanism of action of crisaborole 2% ointment, a topical nonsteroidal PDE4 (phosphodiesterase-4) inhibitor, in a proteomic analysis of 40 adults with mild to moderate AD and 20 healthy subjects.. Within the AD cohort, 2 target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Punch biopsy specimens were collected for biomarker analysis at baseline from all participants, then from AD patients only at day 8 (optional) and day 15.. Compared to the vehicle, crisaborole significantly reversed dysregulation of the overall lesional proteome and of key markers and pathways (eg, Th2, Th17/Th22, and T-cell activation) associated with AD pathogenesis toward both nonlesional and normal skin. Significant clinical correlations were observed with markers associated with nociception and Th2, Th17, and neutrophilic activation.. Study limitations include predominance of white patients in the cohort, relatively short treatment time, and regimented administration of crisaborole.. Our results demonstrate crisaborole-induced normalization of the AD proteome toward a nonlesional molecular phenotype and further support topical PDE4 inhibition in the treatment of mild to moderate AD.

Topics: Adult; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Humans; Ointments; Proteome; Proteomics

Atopic dermatitis is a chronic inflammatory skin disease with a significant impact on the overall wellbeing of patients and their families. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor approved for the treatment of mild-to-moderate atopic dermatitis in multiple countries. However, in the key pivotal trials, a low proportion of the overall patient population was Asian, therefore the safety and efficacy of crisaborole in the Asian population with atopic dermatitis remains unclear. CrisADe CLEAR was a multicenter, randomized, double-blind, vehicle-controlled, phase 3 study (NCT04360187) to assess the efficacy and safety of crisaborole ointment in Chinese and Japanese patients aged ≥2 years with mild-to-moderate atopic dermatitis involving ≥5% treatable body surface area. Patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily for 28 days. The primary endpoint was percentage change from baseline in the Eczema Area and Severity Index total score at day 29. Additional endpoints were improvement and success per Investigator's Static Global Assessment score at day 29 and change from baseline on the Peak Pruritus Numerical Rating Scale at week 4. Safety was assessed using rates of treatment emergent adverse events, serious adverse events, and clinically significant changes in vital signs and clinical laboratory parameters. Crisaborole-treated patients showed a significantly greater reduction versus vehicle in percentage change from baseline in Eczema Area and Severity Index total score at day 29 (P = 0.0002). Response rates for achievement of Investigator's Static Global Assessment improvement and success at day 29 were significantly higher for patients treated with crisaborole versus vehicle (P = 0.0124 and P = 0.0078, respectively). Crisaborole-treated patients showed a significantly greater reduction versus vehicle in change from baseline on the Peak Pruritus Numerical Rating Scale at week 4 (P = 0.0009). No new safety signals were identified. Treatment with crisaborole was effective and well tolerated in Chinese and Japanese patients with mild-to-moderate atopic dermatitis.

Topics: Chronic Disease; Dermatitis, Atopic; Double-Blind Method; East Asian People; Eczema; Humans; Ointments; Phosphodiesterase 4 Inhibitors; Pruritus; Severity of Illness Index; Skin Diseases; Treatment Outcome

Topical treatments for atopic dermatitis (AD) used reactively often fail to achieve lasting disease control; many of these therapies are associated with safety concerns that limit long-term use. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD that has potential as a long-term maintenance therapy.. The aim was to evaluate the long-term efficacy and safety of crisaborole once daily (QD) compared to vehicle QD as a maintenance therapy to reduce the incidence of flares in patients with AD who previously responded to crisaborole twice daily (BID).. CrisADe CONTROL was a randomized, double-blind, vehicle-controlled, 52-week, phase III study of patients aged ≥ 3 months with mild-to-moderate AD involving ≥ 5% treatable body surface area. Eligible patients received crisaborole BID during an open-label run-in period of up to 8 weeks. Responders were randomly assigned in the double-blind maintenance period to receive either crisaborole QD or vehicle QD. Responders were defined as patients who achieved Investigator's Static Global Assessment (ISGA) success (ISGA score of 0 [clear] or 1 [almost clear] with a ≥ 2-grade improvement) and ≥ 50% improvement in Eczema Area and Severity Index total score (EASI-50) from baseline. Patients who experienced a flare (ISGA score ≥ 2) during the double-blind maintenance period switched to crisaborole BID for up to 12 weeks. During this period, patients were assessed every 4 weeks; if the flare resolved (ISGA score ≤ 1), patients resumed their assigned treatment. The primary endpoint was flare-free maintenance until onset of the first flare. Key secondary endpoints were number of flare-free days, number of flares, and maintenance of pruritus response until onset of the first flare. The incidence of treatment-emergent adverse events was also analyzed.. Overall, 497 patients entered the open-label run-in period with crisaborole BID, of which 270 patients were randomized into the 52-week double-blind maintenance period of the study. Of the 270 patients, 135 were randomly assigned to the crisaborole QD group and 135 were randomly assigned to the vehicle QD group. Median time of flare-free maintenance was longer for patients who received crisaborole versus vehicle (111 vs 30 days, respectively; p = 0.0034). The mean number of flare-free days was higher for patients who received crisaborole versus vehicle (234.0 vs 199.4 days, respectively; p = 0.0346). The mean number of flares was lower for patients who received crisaborole versus vehicle (0.95 vs 1.36, respectively; p = 0.0042). No clear trend was observed in maintenance of pruritus response between crisaborole- and vehicle-treated patients. Crisaborole was well tolerated, with no new or unexpected safety findings when used as maintenance treatment.. Crisaborole QD was effective and well tolerated for long-term maintenance treatment and flare reduction in adult and pediatric patients with mild-to-moderate AD.. ClinicalTrials.gov, NCT04040192, 31 July 2019.. Atopic dermatitis (AD) is an immuno-inflammatory skin disease that can last a long time. It causes skin lesions and intense itching. Topical AD treatments used reactively often fail to control the disease over a long period of time. Many are associated with safety concerns that limit long-term use. Crisaborole ointment is a nonsteroidal treatment for the skin and is used to treat mild-to-moderate AD. Previous studies showed that using crisaborole twice daily was effective and had few side effects in patients with mild-to-moderate AD. This study evaluated how effective and safe long-term treatment with once-daily crisaborole was compared with an ointment with no drug (vehicle). The study included patients aged ≥ 3 months with mild-to-moderate AD whose AD improved after previous treatment with twice-daily crisaborole. This study was designed to investigate how much crisaborole reduced the incidence of AD flares over 52 weeks in these patients.The study included 270 patients whose AD had improved after treatment with twice-daily crisaborole. Of these patients, 135 were randomly assigned to receive crisaborole once a day and 135 to receive vehicle once a day. Patients who received crisaborole had a significantly longer time before experiencing AD flares than those who received vehicle. Crisaborole was well tolerated, and no new or unexpected side effects were found when used as a once-daily maintenance treatment for 52 weeks. These results indicate that once-daily treatment with crisaborole could be a potential long-term maintenance treatment option in children and adults with mild-to-moderate AD.

Topics: Adult; Boron Compounds; Child; Dermatitis, Atopic; Double-Blind Method; Humans; Ointments; Pruritus; Severity of Illness Index; Treatment Outcome

Atopic dermatitis (AD) is an inflammatory skin condition with dry, scaly, and intensely itchy skin. Treatment failure is the result of poor adherence.. In this study, we assessed the impact of an internet-based survey on adherence to topical crisaborole 2% ointment in patients with mild AD.. Participants were randomized to the intervention or control group. The intervention group received weekly email surveys regarding adherence for 6 weeks, then monthly for 12 months. All participants came in for 5 visits over the year.. Twenty-eight subjects were recruited for the study (n=19 adults, n=9 pediatrics). Adherence for adults that remained in study (n=6) was 60%. Adherence of the adult control and intervention groups were 49% and 45%, respectively (P>0.05). Adherence for pediatric participants that remained in study (n=2) was 6%. The adherence of the pediatric control and intervention groups were 27% and 29%, respectively (P>0.05).. Medication adherence was low. The survey intervention did not improve adherence. However, more participants in the intervention group completed the study than in the control group of adults. Regular communication from the provider may help patients feel supported and continue treatment.. gov identifier: NCT03250663 J Drugs Dermatol. 2022;21(10):1043-1048. doi:10.36849/JDD.6280.

Topics: Adult; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Dermatitis, Atopic; Dermatologic Agents; Humans; Ointments; Treatment Outcome

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritus, xerosis, and eczematous lesions. In Japan, treatment options, such as topical corticosteroids and tacrolimus, are associated with efficacy and safety concerns. Crisaborole ointment, 2%, is a topical non-steroidal anti-inflammatory agent approved in several countries for the treatment of mild-to-moderate AD. This phase 2b, randomized, double-blind study (NCT03954158) assessed the efficacy and safety of two crisaborole regimens versus vehicle in the treatment of Japanese patients aged ≥2 years with mild-to-moderate AD. Each patient was assigned to one of two age cohorts (≥12 or 2-11 years) and randomized to crisaborole once daily (QD) or twice daily (BID). All patients had two target lesions that were each randomly assigned to crisaborole or vehicle at baseline and treated for 2 weeks. The primary endpoint was change from baseline in total sign score (TSS) in crisaborole- or vehicle-treated target lesions on day 15, and secondary endpoints included change from baseline in Investigator's Static Global Assessment (ISGA) and pruritic assessments (Cohort 1: peak pruritus numeric rating scale [NRS]; Cohort 2: Itch Severity Scale Self-Report and Caregiver-Reported Itch Severity NRS) and incidence of treatment-emergent adverse events (TEAEs). This study comprised 81 patients (Cohort 1: n = 41; Cohort 2: n = 40). Crisaborole-treated lesions showed statistically significant reductions in TSS versus vehicle-treated lesions at day 15 (p < 0.01), and numerically larger decreases in TSS were observed with crisaborole BID versus crisaborole QD in both cohorts. Furthermore, crisaborole-treated lesions generally demonstrated greater decreases in ISGA, peak pruritus NRS, Itch Severity Scale, and Caregiver-Reported Itch Severity NRS versus vehicle-treated lesions irrespective of regimen or cohort. Overall, TEAEs were mild; the most frequently reported TEAEs was application site irritation. In summary, both crisaborole regimens, particularly crisaborole BID, demonstrated efficacy and were well tolerated.

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Humans; Japan; Ointments; Severity of Illness Index; Treatment Outcome

Crisaborole ointment, 2%, is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD). This parallel-cohort, phase 1 study was conducted to investigate skin irritation potential and safety of crisaborole in healthy Japanese adults (cohort 1) and the safety and pharmacokinetic profile of crisaborole and metabolites AN7602 and AN8323 in Japanese adults with mild to moderate AD (cohort 2). In cohort 1, 20 healthy volunteers received single applications of crisaborole and vehicle simultaneously on separate locations under 48-h occlusion. In cohort 2, 12 patients with mild to moderate AD received crisaborole (n = 10) or vehicle (n = 2) twice daily for 8 days. Skin irritation and safety were assessed in cohort 1. Pharmacokinetics and safety were assessed in cohort 2. Skin irritation index (scale 0-400) was 40.0 for crisaborole and 5.0 for vehicle. No treatment-emergent adverse events (TEAE) were reported in cohort 1. The most common TEAE in the crisaborole group in cohort 2 were application site irritation (n = 7) and application site pain (n = 4). Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8 that was comparable with that seen in US-based participants in previous trials. Crisaborole had higher skin irritation than vehicle under occlusion in healthy Japanese adults and had an acceptable safety profile in Japanese adults with mild to moderate AD.

Topics: Administration, Cutaneous; Adult; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Double-Blind Method; Healthy Volunteers; Humans; Male; Middle Aged; Occlusive Dressings; Ointments; Phosphodiesterase 4 Inhibitors; Single-Blind Method; Skin Diseases; Treatment Outcome; Young Adult

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD).. The aim of this study was to evaluate the safety, effectiveness, and pharmacokinetics (PK) of crisaborole in infants aged 3 to < 24 months with mild-to-moderate AD in an open-label study.. Infants (3 to < 24 months) with Investigator's Static Global Assessment (ISGA) of mild (2) or moderate (3) and percentage of treatable body surface area (%BSA) ≥ 5 received crisaborole twice daily for 28 days; a cohort with moderate AD per ISGA and %BSA ≥ 35 were included in a PK analysis. Endpoints included safety (primary), efficacy, and PK (exploratory).. Included were 137 infants total (mean age [SD], 13.6 months [6.42]), with 21 in the PK cohort (12.7 months [6.58]). Treatment-emergent adverse events (TEAEs) were reported for 88 (64.2%) patients (98.9% rated as mild/moderate). TEAEs were considered treatment-related for 22 patients (16.1%); most frequently reported were application site pain (3.6%), application site discomfort (2.9%), and erythema (2.9%). ISGA clear/almost clear with ≥ 2-grade improvement at day 29 was achieved by 30.2% of patients. From baseline to day 29, mean percentage change in Eczema Area and Severity Index score was - 57.5%, and mean change in Patient-Oriented Eczema Measure total score was - 8.5. Crisaborole systemic exposures in infants were characterized and, based on nonlinear regression analysis, were comparable with that in patients aged ≥ 2 years.. In this open-label study, crisaborole was well tolerated and effective in infants (3 to < 24 months) with mild-to-moderate AD with systemic exposures similar to patients aged ≥ 2 years.. NCT03356977.. Atopic dermatitis (AD) is a skin disease that causes inflamed and itchy skin. Crisaborole is an ointment that is approved to treat patients aged 2 years and older with mild-to-moderate AD. This clinical trial studied crisaborole in infants with mild-to-moderate AD who were 3 to under 24 months old. These infants were treated with crisaborole twice a day for 28 days. The trial studied crisaborole’s safety, effectiveness, and absorption into the bloodstream. In total, 137 infants were treated. Although side effects of some sort occurred in about two-thirds of patients, only 1 in 6 patients experienced side effects that were attributed to crisaborole. When these side effects did occur, these were mainly pain, discomfort, or redness where crisaborole was applied. Fewer than 1 in 25 patients experienced each side effect where crisaborole was applied. The doctors saw improvement in the AD symptoms of some patients at day 29 of the study compared to the beginning of the study. Crisaborole blood-level measurements in this age group were consistent with those seen in patients aged 2 years and older. Overall, crisaborole was considered well tolerated and effective in infants (3 to under 24 months old) with mild-to-moderate AD. Safety, Effectiveness, and Pharmacokinetics of Crisaborole in Infants Aged 3 to < 24 Months with Mild-to-Moderate Atopic Dermatitis: An Open-Label, Phase 4 Study (MP4 40891 MB).

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Female; Humans; Infant; Male; Phosphodiesterase 4 Inhibitors; Propylene Glycol; Treatment Outcome

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. This post hoc analysis pools results from 2 phase 3 studies (ClinicalTrials.gov, NCT02118766 [AD-301]; NCT02118792 [AD-302]) to evaluate crisaborole efficacy in patients ≥ 2 years with mild-to-moderate atopic dermatitis (per Investigator's Static Global Assessment) using the Atopic Dermatitis Severity Index (ADSI) and percentage of treatable body surface area (%BSA). Patients were randomly assigned 2:1 to receive crisaborole (n = 1,016) or vehicle (n = 506) twice daily for 28 days. ADSI scores were the sum of pruritus, erythema, exudation, excoriation, and lichenification severity scores, each graded on a 4-point scale from none (0) to severe (3). Respective mean changes in ADSI score and %BSA at day 29 were (crisaborole vs. vehicle) -3.52 versus -2.42 (p < 0.0001) and -7.43 versus -4.44 (p < 0.0001). Crisaborole was effective in treating mild-to-moderate atopic dermatitis based on ADSI and %BSA.

Topics: Body Surface Area; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Double-Blind Method; Humans; Ointments; Severity of Illness Index; Treatment Outcome

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). This pooled post hoc analysis of two phase 3 trials (NCT02118766, NCT02118792) assessed improvement and time to improvement in Investigator's Static Global Assessment (ISGA) and Severity of Pruritus Scale (SPS) outcomes in pediatric patients with mild-to-moderate AD.. Patients aged ≥2 years were randomly assigned 2:1 to receive twice-daily crisaborole or vehicle for 28 days. Patients aged 2-17 years were pooled for this analysis. Proportions of patients and time to achieving ISGA success (clear [0] or almost clear [1] with ≥2-grade improvement from baseline), ISGA clear/almost clear, ≥1-grade improvement in ISGA, SPS success (SPS score ≤1 with ≥1-grade improvement), or ≥1-grade improvement in SPS score were analyzed and stratified by baseline ISGA.. At first postbaseline assessment (day 8), significantly higher proportions of crisaborole- than vehicle-treated patients achieved ISGA success, ISGA clear/almost clear, ≥1-grade ISGA improvement, SPS success, or ≥1-grade improvement in SPS regardless of baseline ISGA. Differences were significantly greater over time for all outcomes for patients with moderate baseline ISGA and numerically greater for those with mild baseline ISGA. Median times to ISGA and SPS outcomes were shorter for crisaborole versus vehicle.. Improvement in ISGA and SPS outcomes were observed with crisaborole in pediatric patients with mild-to-moderate baseline AD.

Topics: Adolescent; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Humans; Ointments; Pruritus; Severity of Illness Index; Treatment Outcome

Atopic dermatitis (AD) is a chronic and recurrent disease presenting with eczematous lesions and pruritus. It impacts patient and family quality of life, increases morbidity, and accounts for large health-care expenditures. Although nonpharmacologic, topical, and systemic treatments exist, management of AD remains challenging due to limited treatment options. Crisaborole is a topical small molecule inhibitor of phosphodiesterase 4 (PDE4), recently approved for the treatment of AD in the United States. Areas covered: The authors review crisaborole in the management of AD based on Phase II, Phase III, and post-marketing studies. Pharmacologic properties such as chemistry, pharmacokinetics, pharmacodynamics and metabolism are discussed. A PubMed systematic review was augmented with Google Scholar searches via keyword, Medical Subject Headings (MeSH), and Boolean operation searches. Expert opinion: Crisaborole showed modest efficacy in short-term trials, but head-to-head trials with topical corticosteroids and tacrolimus are needed to assess its clinical utility. Since crisaborole is non-steroidal, it may reduce the need for topical corticosteroids and address steroid phobia. However, it is likely to suffer from the same factors contributing to intentional non-adherence in topicals: dissatisfaction with efficacy and inconvenience.

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Double-Blind Method; Eczema; Humans

Pruritus is a leading cause of reduced health-related quality of life (QoL) in atopic dermatitis (AD). Crisaborole ointment is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD. In identical Phase 3 studies (NCT02118766, NCT02118792), crisaborole reduced disease and pruritus severity versus vehicle.. Quantify the relationship between pruritus and QoL using data from these studies.. Patients aged ≥2 years were randomly assigned 2 : 1 to receive crisaborole:vehicle twice daily for 28 days. QoL was measured at baseline and day 29 using the Dermatology Life Quality Index (DLQI; patients aged ≥16 years), the Children's Dermatology Life Quality Index (CDLQI; patients aged 2-15 years) and the Dermatitis Family Impact (DFI; caregivers of patients aged 2-17 years). Pruritus was measured using the Severity of Pruritus Scale (SPS), a 4-point scale from 0 ('no itching') to 3 ('bothersome itching/scratching that disturbs sleep'), and captured morning and evening via electronic diary. Data from crisaborole and vehicle arms were pooled for this analysis. A repeated-measures longitudinal model was used to estimate relationships between pruritus (SPS) and QoL (DLQI, CDLQI and DFI in separate analyses).. One thousand five hundred and twenty two patients received crisaborole or vehicle. A linearity assumption for the relationship between SPS and DLQI (n = 294), CDLQI (n = 1200), and DFI (n = 1293) was appropriate. For DLQI, SPS score of 0 was associated with 'no negative effect on patient QoL'; SPS score of 1 was associated with 'small effect on patient QoL'; SPS score of 2 was associated with 'moderate effect on patient QoL'; and SPS score of 3 was associated with 'very large effect on patient QoL'. The pattern of relationships between SPS and CDLQI and DFI was similar.. The relationships between SPS and DLQI, CDLQI and DFI substantiate the significant link between pruritus and patient/caregiver QoL in AD.

Topics: Adolescent; Adult; Aged; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Infant; Male; Middle Aged; Ointments; Pruritus; Quality of Life; Severity of Illness Index

Atopic dermatitis is highly prevalent in black/African American, Asian, and Hispanic patients, making assessment of these populations in clinical trials important. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. In two pivotal phase III clinical trials in patients aged ≥ 2 years, crisaborole was superior to vehicle in reducing global disease severity. The most common treatment-related adverse event was application site pain.. The objective of this study was to investigate the efficacy and safety of crisaborole according to patient race and ethnicity.. A pooled post hoc analysis by race and ethnicity of the two pivotal trials and a safety extension trial was performed. Race included white or nonwhite (encompassing Asian/native Hawaiian/other Pacific Islander, black/African American, and other/American Indian/Alaskan native); ethnicity included Hispanic/Latino or not Hispanic/Latino.. In white, nonwhite, Hispanic/Latino, and not Hispanic/Latino groups at day 29, more crisaborole- than vehicle-treated patients achieved improvements in global disease severity [Investigator's Static Global Assessment of clear/almost clear with a ≥ 2-grade improvement (white: 33.5% vs. 22.3%, nominal p < 0.001; nonwhite: 30.0% vs. 21.3%, nominal p < 0.05; Hispanic/Latino: 35.4% vs. 18.2%, nominal p < 0.01; not Hispanic/Latino: 31.3% vs. 22.8%, nominal p < 0.01)]. Crisaborole treatment also improved atopic dermatitis signs/symptoms and quality of life. Frequency of crisaborole-related adverse events was 7.1-8.5% in the pivotal trials.. Across races and ethnicities, crisaborole demonstrated efficacy for the treatment of mild-to-moderate atopic dermatitis, with a low frequency of treatment-related adverse events.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Ethnicity; Female; Health Status Disparities; Humans; Male; Middle Aged; Ointments; Pain; Pain Measurement; Quality of Life; Racial Groups; Severity of Illness Index; Skin; Time Factors; Treatment Outcome; Young Adult

Phosphodiesterase-4 (PDE4) is a promising target in atopic dermatitis (AD) treatment. The pharmacokinetics (PK), safety, and efficacy of crisaborole topical ointment, 2% (formerly AN2728) (Anacor Pharmaceuticals, Palo Alto, CA), a boron-based benzoxaborole PDE4 inhibitor, were evaluated in children with mild to moderate AD.. This phase 1b, open-label, maximal-use study of crisaborole topical ointment, 2% applied twice daily (dose 3 mg/cm(2) ) for 28 days enrolled patients ages 2 to 17 years with extensive AD involving 25% or more or 35% or more treatable body surface area, depending on age. Primary PK and safety assessments included systemic exposure to crisaborole and its metabolites after 7 days of treatment and the incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy assessments included change from baseline in Investigator Static Global Assessment (ISGA), treatment success (ISGA score ≤1 with a two-grade or greater improvement from baseline), and improvement in five AD signs and symptoms.. Of 34 patients enrolled, 31 completed the study. Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8. Twenty-three of 34 patients reported one or more TEAEs; 95% were mild or moderate and one patient discontinued because of a TEAE. Mean ISGA scores declined from 2.65 at baseline to 1.15 at day 29, 47.1% of patients achieved treatment success, and 64.7% of patients achieved ISGA scores of clear (0) or almost clear . Mean severity scores for AD signs and symptoms declined throughout the study.. This open-label study provides evidence that crisaborole topical ointment, 2% was well tolerated, with limited systemic exposure under maximal-use conditions in patients ages 2 years and older.

Topics: Administration, Topical; Adolescent; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Male; Ointments; Phosphodiesterase 4 Inhibitors; Treatment Outcome

Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks.. We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792).. Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2 years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus.. More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P = .038; AD-302: 31.4% vs 18.0%, P < .001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P = .005; 48.5% vs 29.7%, P < .001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P ≤ .001). Treatment-related adverse events were infrequent and mild to moderate in severity.. Short study duration was a limitation.. Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Cyclic Nucleotide Phosphodiesterases, Type 4; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Ointments; Pruritus; Young Adult

A novel approach for treating atopic dermatitis (AD) is the inhibition of phosphodiesterase 4 (PDE4), an enzyme involved in the proinflammatory cascade. Crisaborole topical ointment, 2% is a novel, boron-based small-molecule PDE4 inhibitor with anti-inflammatory properties. The objective of this proof-of-concept study was to assess the efficacy and safety of crisaborole topical ointment, 2% in adults with mild to moderate AD.. This phase 2a, randomized, double-blind, bilateral, 6-week study of crisaborole topical ointment, 2% was conducted in adult patients with mild to moderate AD with 2 comparable target AD lesions. Patients were randomly assigned to twice-daily application of crisaborole topical ointment, 2% or vehicle, each to 1 of the 2 target lesions. The primary efficacy endpoint was change from baseline in Atopic Dermatitis Severity Index (ADSI) score at day 28. Safety assessments included local tolerability and incidence of adverse events (AEs).. A total of 25 enrolled patients received study medication. At day 28, 17 patients (68%) experienced a greater decrease in ADSI score in the active-treated lesion than in the vehicle-treated lesion; 5 patients (20%) had a greater decrease in ADSI score in the vehicle-treated lesion than in the active-treated lesion. Local application-site reactions were reported in 3 patients (12%). A total of 29 AEs were reported in 11 patients; most (90%) were mild in intensity and unrelated to study medication. No serious or severe AEs were reported, and no patient discontinued due to an AE.. These findings provide preliminary evidence of the efficacy and safety of treatment with crisaborole topical ointment, 2% in adults with mild to moderate AD. The study is registered on ClinicalTrials.gov (identifier NCT01301508).

Topics: Administration, Cutaneous; Adult; Aged; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Severity of Illness Index; Treatment Outcome; Young Adult

Crisaborole is a novel, boron-based, small-molecule, topical phosphodiesterase-4 inhibitor in development for the treatment of patients with mild to moderate atopic dermatitis (AD).. In this multicenter, randomized, double-blind, dose-ranging, phase 2 study, adolescent patients 12 to 17 years of age with mild to moderate AD and 2 distinct target AD lesions were randomized to once-daily (QD) or twice-daily (BID) treatment with crisaborole topical ointment. For each patient, 2 target lesions were randomized to receive 29 days of treatment with 0.5% or 2% crisaborole topical ointment. The primary endpoint was change from baseline in AD severity index (ADSI) score for each lesion. Exploratory efficacy endpoints and safety were also assessed.. A total of 86 patients were enrolled and received crisaborole topical ointment 0.5% or 2% QD (n=44) or BID (n=42). All dosing regimens produced dose-related improvements in ADSI as well as in all 5 component signs and symptoms of AD (erythema, excoriation, exudation, lichenification, and pruritus). The greatest improvements were consistently observed with crisaborole topical ointment, 2% applied BID. With this regimen, ADSI improved from baseline by 71%, and total or partial clearance of target lesions (ADSI ≤ 2) was achieved by 62% of patients after 29 days of treatment. Both doses of crisaborole topical ointment were well tolerated; mild application site reactions were the only treatment-related adverse events (QD, n=3; BID, n=1).. These results provide preliminary evidence of the efficacy and safety of crisaborole topical ointment, 2% applied topically BID in adolescents with mild to moderate AD.

Topics: Administration, Topical; Adolescent; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Dermatitis, Atopic; Dermatologic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Endpoint Determination; Female; Humans; Immunosuppressive Agents; Male; Ointments; Treatment Outcome

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child, Preschool; Dermatitis, Atopic; Hirsutism; Humans; Hypertrichosis; Male; Ointments

Phosphodiesterase 4 (PDE4) is highly expressed in keratinocytes and immune cells and promotes pro-inflammatory responses upon activation. The activity of PDE4 has been attributed to various inflammatory conditions, leading to the development and approval of PDE4 inhibitors as host-directed therapeutics in humans. For example, the topical PDE4 inhibitor, crisaborole, is approved for the treatment of mild-to-moderate atopic dermatitis and has shown efficacy in patients with psoriasis. However, the role of crisaborole in regulating the immunopathogenesis of inflammatory skin diseases and infection is not entirely known. Therefore, we evaluated the effects of crisaborole in multiple mouse models, including psoriasis-like dermatitis, AD-like skin inflammation with and without filaggrin mutations, and Staphylococcus aureus skin infection. We discovered that crisaborole dampens myeloid cells and itch in the skin during psoriasis-like dermatitis. Furthermore, crisaborole was effective in reducing skin inflammation in the context of filaggrin deficiency. Importantly, crisaborole reduced S. aureus skin colonization during AD-like skin inflammation. However, crisaborole was not efficacious in treating S. aureus skin infections, even as adjunctive therapy to antibiotics. Taken together, we found that crisaborole reduced itch during psoriasis-like dermatitis and decreased S. aureus skin colonization upon AD-like skin inflammation, which act as additional mechanisms by which crisaborole dampens the immunopathogenesis in mouse models of inflammatory skin diseases. Further examination is warranted to translate these preclinical findings to human disease.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cyclic Nucleotide Phosphodiesterases, Type 4; Dermatitis, Atopic; Disease Models, Animal; Filaggrin Proteins; Humans; Inflammation; Mice; Phosphodiesterase 4 Inhibitors; Pruritus; Psoriasis; Staphylococcal Infections; Staphylococcus aureus

Topics: Administration, Cutaneous; Dermatitis, Atopic; Humans; Ointments; Treatment Outcome; Vitiligo

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Dermatitis, Allergic Contact; Dermatitis, Atopic; Humans

The present work aims to formulate nanoemulgel of crisaborole (CB) and evaluate its effectiveness against 2,4-Di-nitrochlorobenzene induced (DNCB) atopic dermatitis (AD) in mice.. AD is a chronic inflammation of the skin affecting the quality of life. CB is a topical PDE4 inhibitor marketed as a 2% ointment. It, however, possesses poor aqueous solubility. An o/w nanoemulsion shall exhibit an enhanced therapeutic effect owing to the increased solubility of CB and an augmented skin penetration. The addition of a gelling agent to form a nanoemulgel further provides ease of application to the patients.. NE 9 comprised of 7.49% oil, 37.45% S. We can thereby conclude that nanoemulgel formulation can be a successful drug delivery strategy for enhancing the therapeutic effect of CB.

Topics: Animals; Dermatitis, Atopic; Disease Models, Animal; Emulsions; Mice; Nanoparticles; Ointments; Quality of Life

Crisaborole, a phosphodiesterase 4 (PDE4) inhibitor, has been approved for the treatment of mild to moderate atopic dermatitis. Atopic dermatitis is often associated with increased pain. Using a mouse model, this study investigated whether crisaborole suppresses pain associated with atopic dermatitis and the potential mechanisms underlying it. The mouse model for atopic dermatitis was developed by repeatedly applying MC903. MC903-treated mice had increased spontaneous scratching (itch-related behaviour) and wiping behaviour (pain-related behaviour). Crisaborole was topically applied to the cheek skin of MC903-treated mice, and it reduced both itch- and pain-related behaviours in these mice. Immunofluorescence staining revealed that crisaborole reduced neutrophil infiltration and interaction of neutrophils with sensory neurones. Intradermal injection of S100A8/A9, proinflammatory neutrophil mediator, enhanced not only itch-related behaviours evoked by histamine or chloroquine, but also pain-related behaviours evoked by capsaicin. Calcium imaging of mouse dorsal root ganglion neurones revealed that pretreatment with S100A8/A9 significantly increased calcium responses to histamine and capsaicin, and the proportion of chloroquine-sensitive neurones. These findings suggest that the PDE4 inhibitor reduces itch and pain, in part by inhibiting infiltration of S100A8/A9-containing neutrophils in a mouse model of MC903-induced atopic dermatitis.

Topics: Animals; Calcium; Capsaicin; Chloroquine; Dermatitis, Atopic; Disease Models, Animal; Histamine; Neutrophil Infiltration; Pain; Pruritus

This post hoc analysis of pooled data from two phase III studies (AD-301: NCT02118766; AD-302: NCT02118792) explored the efficacy and safety of crisaborole ointment, 2%, a nonsteroidal phosphodiesterase 4 inhibitor, for the treatment of mild-to-moderate atopic dermatitis (AD) in pediatric patients (aged 2 to < 18 years) only, stratified by baseline characteristics.. Pediatric patients with mild or moderate AD per Investigator's Static Global Assessment (ISGA) and percentage of treatable body surface area (%BSA) ≥ 5 at baseline were assessed. Crisaborole or vehicle (2:1 randomization ratio) was applied twice daily for 28 days. Of the 1313 pediatric patients included in this study, 874 received crisaborole and 439 received vehicle. ISGA success was defined as clear (0) or almost clear (1) with ≥ 2-grade improvement from baseline. Efficacy and safety were stratified by age group, sex, baseline ISGA, baseline %BSA per published severity strata, and prior AD therapy.. Overall, the proportions of crisaborole-treated and vehicle-treated pediatric patients with ISGA success at week 4 were 32.5 and 21.5%, respectively. ISGA success rates at day 29 (week 4) were generally higher in crisaborole-treated (21.9-38.1%) than vehicle-treated (15.7-26.9%) patients across subgroups. Rates of treatment-related application site pain were 2.4-10.1% for crisaborole-treated patients and 0.6-2.2% for vehicle-treated patients across subgroups. No new safety concerns were noted in any patient subgroup.. Crisaborole improved global disease severity and was reasonably well tolerated across all pediatric baseline characteristic subgroups. Application site discomfort was greater with crisaborole than with vehicle, but few patients discontinued treatment.. NCT02118766; NCT02118792 (registration date: April 21, 2014).. Crisaborole is an ointment approved for the treatment of mild-to-moderate eczema. In two phase III clinical trials, eczema improved after 28 days of crisaborole use in patients aged ≥ 2 years. Patients with eczema rashes used crisaborole or plain ointment twice a day for 28 days. The clinical trials excluded patients with serious infections. Eczema treatment within 2 weeks of the trials was not allowed. We looked at whether traits of children aged 2–17 years affected how well crisaborole improved eczema. We studied boys and girls by age and how bad their eczema was at the start of the study. We combined data from both clinical trials to calculate the percentages of children with clear or almost clear skin at day 29. We also studied the frequency of side effects at day 29. After 4 weeks, 33% of children receiving crisaborole compared with 22% of children receiving plain ointment had clear or almost clear skin, a meaningful difference in favor of crisaborole. This was also true across groups. Most patients did not have side effects related to crisaborole. The most common side effect related to crisaborole was application site pain. This side effect occurred in up to one in ten children receiving crisaborole. Up to 1 in 50 patients receiving plain ointment had application site pain. Few children stopped crisaborole treatment, and there were no new safety concerns. In conclusion, compared with plain ointment, crisaborole improved eczema in more children, and side effects were minor.

Topics: Adolescent; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Dermatitis, Atopic; Humans; Ointments; Treatment Outcome

Topics: Dermatitis, Atopic; Erythema; Humans; Ointments; Treatment Outcome

In this work, a series of structurally novel benzoxaborole derivatives were designed, synthesized and biologically evaluated as PDE4 inhibitors for battling atopic dermatitis (AD). Among them, the majority exhibited superior PDE4B inhibitory activities to that of the lead compound Crisaborole, an approved PDE4 inhibitor. In particular, 72, the most potent PDE4B inhibitor throughout this series, displayed 136-fold improved enzymatic activity (IC

Topics: Animals; Boron Compounds; Calcitriol; Cyclic Nucleotide Phosphodiesterases, Type 4; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Design; Edema; Female; Guinea Pigs; Male; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Molecular Structure; Phosphodiesterase 4 Inhibitors; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tetradecanoylphorbol Acetate

Topics: Asthma; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Clinical Trials, Phase III as Topic; Dermatitis, Atopic; Double-Blind Method; Food Hypersensitivity; Humans; Ointments; Rhinitis, Allergic; Treatment Outcome

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory condition marked by pruritus and traditionally treated with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Crisaborole 2% ointment (a topical phosphodiesterase-4 inhibitor) is a newer topical agent for the treatment of AD. Crisaborole is indicated for treating mild-to-moderate AD and evidence from phase 3 and phase 4 trials show that crisaborole is an effective agent with a well-tolerated side effect profile for children >2 years of age. The most common side effects are pain and paresthesia at the application site. Treatments with tolerable safety profiles such as crisaborole may provide an alternative to patients with TCS phobia. The role of crisaborole in AD therapy may become clearer as multiple phase 4 trials are currently underway and their results are poised to answer more questions, including its safety profile for patients as young as 3 months of age, potential use as a steroid-sparing agent, and direct comparisons to TCS and TCI, which are the current mainstay treatments of mild-to-moderate AD.

Topics: Administration, Cutaneous; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatologic Agents; Humans

Topics: Animals; Anti-Inflammatory Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatophagoides farinae; Disease Models, Animal; Female; Humans; Leukocytes, Mononuclear; Mice; Oxazoles; Oxazolone; Phosphodiesterase 4 Inhibitors; Piperazines; Severity of Illness Index; Skin; Thiazoles

Crisaborole ointment, 2%, is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. It contains 9% w/w propylene glycol (PG). Although PG is generally considered to be safe when used as a pharmaceutical excipient or food additive, the European Medicines Agency has recommended maximum daily limits for PG exposure. To determine the potential skin permeation of PG from crisaborole ointment, ex vivo human skin (normal abdominal skin from healthy volunteers without atopic dermatitis) and in vivo minipig experiments (dermal application on unabraded or abraded skin) were performed. Over a 24-h period, the extent of PG permeation in the ex vivo human skin experiment was 3.7% for crisaborole ointment. In the in vivo minipig study, the bioavailability of PG after dermally applied crisaborole ointment was 3.56% for unabraded skin and 3.65% for abraded skin. Experimental values from this study can serve to provide scientific justification for using a product's specific absorption value, as opposed to a maximum absorption of 100%, when attempting to estimate systemic exposure of PG from a topical product.

Topics: Administration, Cutaneous; Animals; Biological Availability; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Male; Middle Aged; Ointments; Permeability; Propylene Glycol; Skin; Skin Absorption; Swine; Swine, Miniature

To characterize primary care providers' (PCPs) practice patterns for atopic dermatitis (AD) in children <2 years old and determine the need for AD guidelines for PCPs focused on this age group.. This is a mixed-methods study consisting of a survey and a retrospective medical record review of PCP practices in the Chicago metropolitan area. The survey was analyzed using both quantitative and qualitative methods.. In the survey (n = 52 respondents), PCPs reported management of AD is different in children <2 years compared with older children (88%). They were more likely to refer to a specialist (65%) and less likely to use high-potency topical corticosteroids (64%). In the chart review, PCP visits for children 2-5 years old (n = 50 914) vs those <2 years old (n = 71 913) for AD, older children had medium- and high-potency topical corticosteroids prescribed more frequently than younger children (0.66% vs 0.37%, P < .01 and .15% vs 0.05%, P < .01, respectively). In the subset of children <2 years of age who also were evaluated by a specialist (n = 109), medium- and high-potency topical corticosteroids were prescribed disproportionately at visits to providers in dermatology (57%) vs allergy (30%) vs pediatrics (15%) (P < .01). PCPs suggested that guidelines for this age group should include recommendations for preferred corticosteroids (39%), allergy management (35%), referral criteria (22%), and assessment of disease severity (11%).. PCP management of AD in children <2 years is different from older children, with possible underuse of medium/high-potency topical corticosteroids. Clear guidelines for this age group are needed.

Topics: Administration, Topical; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Child, Preschool; Dermatitis, Atopic; Drug Prescriptions; Female; Glucocorticoids; Humans; Male; Pediatricians; Practice Patterns, Physicians'; Primary Health Care; Referral and Consultation; Retrospective Studies; Severity of Illness Index; Surveys and Questionnaires; United States

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Drug Evaluation, Preclinical; Drug Therapy, Combination; Emollients; Humans; Permeability; Skin; Skin Cream

Clinical trial data for dupilumab, a monoclonal antibody against the interleukin-4 receptor (IL-4Rα), have shown that it is safe and effective for the treatment of moderate to severe atopic dermatitis in patients whose disease is resistant to other therapies. However, little real-world experience with dupilumab use has been reported thus far. The aim of this retrospective study was to assess overall outcomes in adult patients with atopic dermatitis (AD) treated with dupilumab.. A retrospective review of electronic medical records was conducted for patients treated with dupilumab in the Department of Dermatology at the University of California, Irvine.. We analyzed the medical records of 77 AD patients who received dupilumab according to standard dosing and had at least one documented follow-up visit. In 66 patients (86%), dupilumab improved clinical disease severity, with 23 patients (30%) experiencing complete clearance on dupilumab. Dupilumab was generally well-tolerated and caused no serious adverse events. The most common side effects included dry eyes, conjunctivitis, and keratitis. The most common reason for discontinuation of treatment was lack of substantial clinical improvement or progression of disease severity, followed by ophthalmologic side effects.. Overall, dupilumab was well-tolerated and resulted in clinical improvement in our patient population. These results provide additional important information on the safety and utility of dupilumab treatment for moderate to severe atopic dermatitis in the real-world clinical setting.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal, Humanized; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Combined Modality Therapy; Conjunctivitis; Dermatitis, Atopic; Dermatologic Agents; Disease Progression; Drug Therapy, Combination; Dry Eye Syndromes; Female; Humans; Keratitis; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Treatment Outcome; Ultraviolet Therapy

Topics: Administration, Cutaneous; Adolescent; Adult; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Dermatitis, Atopic; Face; Female; Humans; Male; Middle Aged; Pain; Phosphodiesterase 4 Inhibitors; Retrospective Studies; Young Adult

Topics: Adult; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Cyclic Nucleotide Phosphodiesterases, Type 4; Dermatitis, Atopic; Humans

To assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, for the treatment of mild or moderate atopic dermatitis (AD) in two phase III studies (AD-301 and AD-302).. Two identically designed multicentre, double-blind randomized controlled trials were conducted in the U.S.A. Participants were randomized 2 : 1 to receive crisaborole or vehicle treatment. In total 47 and 42 investigational centres were identified for AD-301 and AD-302, respectively.. Inclusion criteria were identified as age ≥ 2 years, clinical diagnosis of AD (as per the Hanifin and Rajka criteria), ≥ 5% body surface area involvement, and baseline Investigator's Static Global Assessment (ISGA) mild or moderate. Exclusion criteria included previous use of biologics or systemic corticosteroids (within the last 28 days) or a topical calcineurin inhibitor/corticosteroid (within the last 14 days), and active skin infection.. Participants were instructed to apply the study drug twice daily to all lesions identified at baseline, and all new lesions identified after day 1 (with weekly review of application instructions). Bland emollients were permitted to be used on skin not treated with the study drug.. The primary outcome was defined as ISGA clear or almost clear at day 29, with a 2-grade or more improvement from baseline.. Secondary outcomes included the proportion of patients with an ISGA score of clear or almost clear at day 29, and time to success in ISGA score. Additional outcomes included pruritus severity and signs of AD (erythema, exudation, excoriation, induration/papulation and lichenification), and were measured on a 4-point scale (none, mild, moderate, severe). Adverse events were also recorded.. More participants in the crisaborole-treated group achieved ISGA scores of clear or almost clear with ≥ 2-grade improvement than in the vehicle-treated group (AD-301, 32·8% vs. 25·4%, P = 0·38; AD-302, 31·4% vs. 18·0%, P < 0·001). Greater percentages of clear and almost clear scores were observed in the treatment groups (51·7% vs. 40·6%, P = 0·005; 48·5% vs. 29·7%; P < 0·001), as well as earlier success in ISGA score and improvement in pruritus (P ≤ 0·001). No serious treatment-related adverse events were identified.. Based on the study results, the authors suggest that crisaborole is a safe treatment that improves disease severity, pruritus and clinical signs associated with AD.

Topics: Adult; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Cyclic Nucleotide Phosphodiesterases, Type 4; Dermatitis, Atopic; Double-Blind Method; Humans; Ointments; Phosphodiesterase 4 Inhibitors; Treatment Outcome

The implementation of treatment guidelines for atopic dermatitis is challenging, in part because of different guidance documents being used by different groups of specialists and in part because the language of guidelines often reflects the evidence base rather than the practical "how to." The Atopic Dermatitis Yardstick is part of a series developed in response to the need to proactively address the loss of disease control for atopic illnesses at all levels of severity. It presents a comprehensive update on how to conduct a sustained step-up in therapy for the patient with inadequately controlled or poorly controlled atopic dermatitis. Patient profiles, based on current guidelines and the authors' combined clinical experience, provide a practical and clinically meaningful guide to aid physicians in helping their patients achieve the goal of clear to almost clear. The intent is not to replace guidelines but to complement their recommendations incorporating the latest research and therapies.

Topics: Adult; Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Clinical Decision-Making; Cyclic Nucleotide Phosphodiesterases, Type 4; Dermatitis, Atopic; Emollients; Evidence-Based Medicine; Humans; Phototherapy; Practice Guidelines as Topic; Quality of Life; Research Design

Topics: Administration, Topical; Adult; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Dermatitis, Atopic; Eczema; Humans; Tacrolimus

Atopic dermatitis (AD), a chronic inflammatory skin disease, is often treated with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Crisaborole ointment is a non-steroidal, phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD. In December 2016, crisaborole was approved in the US for mild-to-moderate AD in patients ≥2 years of age.. To evaluate real-world utilization and cost of TCS and TCI in the US and estimate the budget impact of crisaborole over 2 years from a third-party payer perspective.. TCS and TCI prescriptions in 2015 for patients ≥2 years of age with ≥1 AD diagnosis in the Truven Health Analytics MarketScan Commercial and Medicare Supplemental Research Databases were analyzed for patients receiving TCI or TCS alone or in combination (TCS/TCI population) and patients receiving TCI alone or in combination with TCS (TCI population). A budget impact model used TCS and TCI market shares, annual use, and cost per prescription. Crisaborole uptake rates of 4.7% (TCS) and 20.2% (TCI), with an annual increase of 1% in year 2, were assumed. Budget impact was calculated as total and per-member-per-month (PMPM) cost over 2 years for a health plan of 1 million members.. Annual prescriptions/patient ranged from 1.36-6.41; annual cost/patient was $53-$1,465. The budget impact of crisaborole over 2 years in the TCS/TCI population was $350,946 (PMPM, $0.015), with increases of $162,106 in year 1 (PMPM, $0.014) and $188,841 in year 2 (PMPM, $0.016). The budget impact in the TCI population was -$22,871, with decreases of $11,160 in year 1 and $11,712 in year 2 (each PMPM, -$0.001). For both populations, one-way sensitivity analyses showed that budget impact was most sensitive to changes in crisaborole cost and annual use.. From US payer perspectives, adoption of crisaborole results in modest pharmacy budget impact/savings.

Topics: Administration, Cutaneous; Adolescent; Adrenal Cortex Hormones; Adult; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Budgets; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Male; Middle Aged; Models, Econometric; Ointments; Phosphodiesterase 4 Inhibitors; United States; Young Adult

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatologic Agents; Humans

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunologic Factors; Quality of Life

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Therapy; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Humans; Ointments

Long-term topical treatment is often required for atopic dermatitis (AD), a chronic inflammatory skin disease.. To assess the long-term safety results from a multicenter, open-label, 48-week safety study (AD-303) of patients (N = 517) ≥2 years of age with mild to moderate AD who continued crisaborole treatment, a topical phosphodiesterase-4 inhibitor, after completing a 28-day phase 3 pivotal study (AD-301, AD-302).. Global disease severity was assessed in patients every 4 weeks, and if assessed as mild or greater, a 28-day treatment period with crisaborole applied twice daily was initiated. Adverse events (AEs), including treatment-emergent AEs (TEAEs), and serious AEs were analyzed.. During the pivotal studies and AD-303, 65% of patients reported ≥1 TEAE, most of which were mild (51.2%) or moderate (44.6%) and considered unrelated to treatment (93.1%). The frequency and severity of TEAEs were consistent. The most frequently reported treatment-related AEs (overall, 10.2%) were dermatitis atopic (3.1%), application-site pain (2.3%), and application-site infection (1.2%). Nine patients (1.7%) discontinued the long-term study because of TEAEs.. Long-term efficacy was not analyzed.. Crisaborole ointment had a low frequency of treatment-related AEs over 48 weeks of treatment of patients with AD.

Topics: Adolescent; Adult; Aged; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Disease Progression; Female; Humans; Infections; Male; Middle Aged; Ointments; Pain; Phosphodiesterase 4 Inhibitors; Severity of Illness Index; Symptom Flare Up; Young Adult

Topics: Administration, Cutaneous; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatologic Agents; Humans

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

Psoriasis and atopic dermatitis are skin diseases affecting millions of patients. Here, we characterize benzoxaborole phosphodiesterase (PDE)-4 inhibitors, a new topical class that has demonstrated therapeutic benefit for psoriasis and atopic dermatitis in phase 2 or phase 3 studies. Crisaborole [AN2728, 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile], compd2 [2-ethoxy-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)nicotinonitrile], compd3 [6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-(2-isopropoxyethoxy)nicotinonitrile], and compd4 [5-chloro-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-((4-oxopentyl)oxy)nicotinonitrile] are potent PDE4 inhibitors with similar affinity for PDE4 isoforms and equivalent inhibition on the catalytic domain and the full-length enzyme. These benzoxaboroles are less active on other PDE isozymes. Compd4 binds to the catalytic domain of PDE4B2 with the oxaborole group chelating the catalytic bimetal and overlapping with the phosphate in cAMP during substrate hydrolysis, and the interaction extends into the adenine pocket. In cell culture, benzoxaborole PDE4 inhibitors suppress the release of tumor necrosis factor-α, interleukin (IL)-23, IL-17, interferon-γ, IL-4, IL-5, IL-13, and IL-22, and these cytokines contribute to the pathologic changes in skin structure and barrier functions as well as immune dysregulation in atopic dermatitis and psoriasis. Treatment with compd3 or N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate increases cAMP response element binding protein phosphorylation in human monocytes and decreases extracellular signal-regulated kinase phosphorylation in human T cells; these changes lead to reduced cytokine production and are among the mechanisms by which compd3 blocks cytokine release. Topical compd3 penetrates the skin and suppresses phorbol myristate acetate-induced IL-13, IL-22, IL-17F, and IL-23 transcription and calcipotriol-induced thymic stromal lymphopoietin expression in mouse skin. Skin thinning is a major dose-limiting side effect of glucocorticoids. By contrast, repeated application of compd3 did not thin mouse skin. These findings show the potential benefits and safety of benzoxaborole PDE4 inhibitors for the treatment of psoriasis and atopic dermatitis.

Topics: Administration, Topical; Animals; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Catalytic Domain; Cyclic AMP Response Element-Binding Protein; Cyclic Nucleotide Phosphodiesterases, Type 4; Cytokines; Dermatitis, Atopic; Female; Gene Expression Regulation; Leukocytes; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Molecular; Phosphodiesterase 4 Inhibitors; Phosphorylation; Psoriasis; Skin; Thymic Stromal Lymphopoietin

A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatologic Agents; Edema; Humans; Mice; Psoriasis; Structure-Activity Relationship; U937 Cells