stilbenes and Dermatitis--Atopic

Tapinarof is a topical, aryl-hydrocarbon receptor agonist that has recently received FDA-approval for the treatment of psoriasis. This novel therapeutic has also been shown to be effective for atopic dermatitis and is currently in phase 3 for this indication. Beyond good efficacy and fast onset of action in patients with psoriasis, the clinical response to tapinarof is notable for durable remission or near remission, maintained for an average of 130 days beyond treatment discontinuation in patients with psoriasis in phase 3 studies. Tapinarof is usually well tolerated but can induce a follicular inflammatory reaction and dermatitis in some patients. This narrative review covers the historical development of this molecule, safety and efficacy data from clinical trials conducted with various topical formulations, and practical considerations derived from our 15 years of clinical trial experience with the drug.

Topics: Dermatitis, Atopic; Humans; Psoriasis; Resorcinols; Stilbenes

Since its introduction in 1952, topical glucocorticosteroids remain the initial and long-term treatment option for various forms of inflammatory dermatitis. A number of non-steroidal topicals for treating inflammatory dermatoses have been developed in the recent decades (such as topical calcineurin inhibitors, vitamin D analogues, and phophodiesterase-4 inhibitors), but none had the combination of broad therapeutic range, relatively rapid onset of action, high tolerability, and wide-spread clinical success; this allowed topical glucocorticosteroids to remain the mainstay of therapy. This situation has shifted dramatically, with three non-steroidal new molecular entities, each with completely different mechanisms of action, receiving approval of the Food and Drug Administration (FDA) in the past year. Topical ruxolitinib, a Janus kinase (JAK) inhibitor, was approved by the FDA in September 2021 for atopic dermatitis, and was the subject of the first report in this review series. Subsequently, topical tapinarof, an aryl hydrocarbon receptor modulating agent, was approved by the FDA in May 2022 for treating plaque psoriasis, and is the focus of this present report. Finally and the most recently, topical roflumilast, a highly potent phosphodiesterase-4 inhibitor, received FDA approval in July 2022 for treating plaque psoriasis, and is reviewed in the third and final report in this series. In addition to their unique mechanisms of action and spectra of activity, each of these agents has unique clinical characteristics, including degree of efficacy, rapidity of onset of efficacy, potential remittive effects, and safety and tolerability profiles. In short, in this three-part series, we reviewed and summarized the data surrounding each agent, providing a comprehensive overview which would allow dermatologists to confidently and appropriately integrate them into treatment paradigms.

Topics: Dermatitis, Atopic; Humans; Psoriasis; Resorcinols; Stilbenes; United States

Tapinarof cream 1% (VTAMA

Topics: Adult; Dermatitis, Atopic; Humans; Psoriasis; Resorcinols; Stilbenes

Atopic dermatitis (AD) is an eczematous, pruritic skin disorder with extensive barrier dysfunction and elevated interleukin (IL)-4 and IL-13 signatures. The barrier dysfunction correlates with the downregulation of barrier-related molecules such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL). IL-4 and IL-13 potently inhibit the expression of these molecules by activating signal transducer and activator of transcription (STAT)6 and STAT3. In addition to IL-4 and IL-13, IL-22 and IL-17A are probably involved in the barrier dysfunction by inhibiting the expression of these barrier-related molecules. In contrast, natural or medicinal ligands for aryl hydrocarbon receptor (AHR) are potent upregulators of FLG, LOR, and IVL expression. As IL-4, IL-13, IL-22, and IL-17A are all capable of inducing oxidative stress, antioxidative AHR agonists such as coal tar, glyteer, and tapinarof exert particular therapeutic efficacy for AD. These antioxidative AHR ligands are known to activate an antioxidative transcription factor, nuclear factor E2-related factor 2 (NRF2). This article focuses on the mechanisms by which FLG, LOR, and IVL expression is regulated by IL-4, IL-13, IL-22, and IL-17A. The author also summarizes how AHR and NRF2 dual activators exert their beneficial effects in the treatment of AD.

Topics: Antioxidants; Basic Helix-Loop-Helix Transcription Factors; Coal Tar; Dermatitis, Atopic; Filaggrin Proteins; Gene Expression Regulation; Humans; Interleukin-13; Interleukin-17; Interleukin-22; Interleukin-4; Interleukins; Membrane Proteins; NF-E2-Related Factor 2; Oxidative Stress; Protein Precursors; Receptors, Aryl Hydrocarbon; Resorcinols; S100 Proteins; Signal Transduction; Skin; STAT3 Transcription Factor; STAT6 Transcription Factor; Stilbenes; Tars

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

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

Topics: Dermatitis, Atopic; Double-Blind Method; Humans; Resorcinols; Severity of Illness Index; Stilbenes; Treatment Outcome

Tapinarof is a topical therapeutic aryl hydrocarbon receptor modulating agent under investigation for atopic dermatitis (AD) and psoriasis treatment.. A phase 2b, double-blind, vehicle-controlled study randomly assigned adolescents and adults with AD to receive tapinarof cream 0.5%, 1%, or vehicle, once or twice daily, for 12 weeks with a 4-week follow-up. Outcomes included Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), body surface area affected, pruritus numeric rating scale scores, patients' impressions of AD and pruritus symptom severity, and Patient-Oriented Eczema Measure (POEM) scores.. Overall, 191 of 247 randomized patients completed the study. Week 12 IGA responses were higher in the tapinarof groups versus the vehicle group, reaching statistical significance with tapinarof 1% twice daily, ≥75%/90% improvement in EASI from baseline were significantly higher in the tapinarof groups (except 0.5% once daily and 0.5% twice daily), EASI scores were significantly improved in all tapinarof groups, and body surface area affected was significantly reduced in the tapinarof groups (except 0.5% twice daily). More patients reported AD and pruritus symptom severity as very/moderately improved in tapinarof groups, and POEM improvements were observed in all groups. Most adverse events were mild or moderate.. Larger prospective studies are required to confirm the reported analyses.. Tapinarof is a potential important advance in topical medicine development for AD.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Child; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Patient Reported Outcome Measures; Resorcinols; Severity of Illness Index; Skin Cream; Stilbenes; Treatment Outcome; Young Adult

Safe and efficacious topical treatments are needed for atopic dermatitis (AD).. We assessed the safety and efficacy of tapinarof cream (2 concentrations and 2 application frequencies) in patients with AD.. A double-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in patients age 12 to 65 years, with body surface area involvement of at least 5% to 35% and an Investigator's Global Assessment score of 3 or higher (moderate to severe) at baseline. Primary end points included an Investigator's Global Assessment score of clear or almost clear (0 or 1) and a minimum 2-grade improvement (treatment success) at week 12. Secondary analyses included a 75% or greater improvement in Eczema Area and Severity Index score, reduction of numeric rating scale (NRS) score for itch from baseline, and other prespecified end points.. The rates of treatment success with tapinarof cream at week 12 were 53% (a concentration of 1% twice daily), 46% (a concentration of 1% once daily), 37% (a concentration of 0.5% twice daily), 34% (0.5% once daily), 24% (vehicle twice daily), and 28% (vehicle once daily). The rate with a concentration of 1% twice daily (53%) was statistically significantly higher than the rate with vehicle twice daily (24%). Treatment success was maintained for 4 weeks after the end of tapinarof treatment. The rate of treatment-emergent adverse events was higher with tapinarof (93 of 165 [56%]) than with vehicle (34 of 82 [41%]), and the events were mild to moderate in intensity.. Large confirmation trials are needed.. Tapinarof cream is efficacious and well tolerated in adolescent and adult patients with AD.

Topics: Adolescent; Adult; Aged; Child; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Male; Middle Aged; Resorcinols; Skin Cream; Stilbenes; Young Adult

Tapinarof cream is a novel topical nonsteroidal agent that represents a unique class of anti-inflammatory molecules targeting the aryl hydrocarbon receptor. Study 201851 was an open-label, 2-cohort sequential study that assessed the systemic pharmacokinetics, safety, and efficacy of tapinarof in adults with moderate to severe atopic dermatitis. A total of 11 participants were enrolled: 5 received 2% cream, and 6 received 1% cream. Tapinarof was systemically absorbed, and measurable amounts were detected in both cohorts. Generally, plasma exposure was greater with the 2% cream and decreased from day 1 to day 21. Median T

Topics: Administration, Topical; Adult; Dermatitis, Atopic; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Resorcinols; Stilbenes; Treatment Outcome; Young Adult

GSK2894512 is a topically delivered investigational drug being developed for treatment of atopic dermatitis and psoriasis.. To investigate, in a phase I clinical trial, the spatial biodistribution and residency of GSK2894512 within the epidermis and dermis of healthy human participants noninvasively using fluorescence lifetime imaging microscopy (FLIM).. Two topical drug formulations containing GSK2894512 1% were applied to the right and left forearms of six participants for seven consecutive days, followed by seven days of observation for residency. FLIM images were obtained daily throughout the study, approximately every 24 h. During the treatment phase of the study, images were collected from each participant pretreatment, reflecting the residual dose from the previous day. Three punch biopsies from each participant of one formulation was obtained from the treated region during the post-treatment follow-up period between days 8 and 14 for comparison with FLIM results.. Cellular and subcellular features associated with different epidermal and dermal layers were visualized noninvasively, down to a depth of 200 μm. Results yielded three-dimensional maps of GSK2894512 spatial distribution and residency over time. This fluorescence data provided a marker that was used as a monitor for day-to-day variance of drug presence and residency postapplication.. The results suggest FLIM could be a viable alternative to skin biopsies without the usual patient discomfort and limitations, thereby enabling the direct measurement of skin distribution through longitudinal monitoring. These results are the first step in establishing the unique capabilities that multiphoton imaging could provide to patients through noninvasive drug detection.

Topics: Administration, Cutaneous; Adult; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Dermatologic Agents; Dermis; Epidermis; Healthy Volunteers; Humans; Intravital Microscopy; Male; Microscopy, Fluorescence, Multiphoton; Psoriasis; Resorcinols; Skin Cream; Stilbenes; Tissue Distribution; Young Adult

There is a need for the development of novel nonsteroidal topical drugs for the treatment of atopic dermatitis (AD).. The primary objective was to evaluate the efficacy of WBI-1001 over 6 weeks of treatment of mild to severe AD..   Patients with AD affecting 3-20% of their body surface area and with an Investigator's Global Assessment (IGA) of 2-4 were randomized (1 : 1 : 1) to receive placebo, WBI-1001 0·5% or WBI-1001 1·0% in a cream formulation applied twice daily for 6 weeks. At the end of this phase, patients receiving WBI-1001 continued the same treatment for an additional 6 weeks. Patients receiving placebo entered into a 6-week double-blind phase with re-randomization (1 : 1) to WBI-1001 0·5% or 1·0% cream. The primary objective was to evaluate the efficacy of WBI-1001 over 6 weeks of treatment of mild to severe AD. The primary endpoint was the mean change from baseline in IGA at day 42 (week 6).. In total, 148 patients were randomized and analysed in the placebo (51), WBI-1001 0·5% (50) and WBI-1001 1·0% (47) groups. There was a decrease of 1·3 [43%; P < 0·001; 95% confidence interval (CI) -1·2 to -0·5] and 1·8 (56·3%; P < 0·001; 95% CI -1·6 to -0·9) in IGA at day 42 in the WBI-1001 0·5% and 1·0% groups, respectively, as compared with a decrease of 0·5 (14·7%) in the placebo group. Adverse drug reactions included a few cases of folliculitis and contact dermatitis.. WBI-1001 is an efficacious novel topical anti-inflammatory molecule for the treatment of AD.

Topics: Administration, Cutaneous; Adult; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Dermatitis, Atopic; Dose-Response Relationship, Drug; Double-Blind Method; Eczema; Female; Humans; Male; Middle Aged; Ointments; Resorcinols; Severity of Illness Index; Stilbenes; Treatment Outcome; Young Adult

Atopic dermatitis (AD) is one of the most prevalent chronic skin inflammatory disorders requiring continuous treatment and care. Pterostilbene (PTN) belongs to stilbene and is a polyphenolic compound of natural origin. It is similar to resveratrol and has analogous anti-inflammatory, anti-oxidant, and anti-carcinogenic characteristics. This study was intended to evaluate the effect of PTN against atopic dermatitis. The disease was induced by sensitization with 2,4-dinitrochlorobenzene (DNCB) in mice. The standard control group (SCG) received topical 0.1% tacrolimus (TC), whereas three other treatment groups received daily topical PTN at 0.2, 0.6, and 1% w/w for 28 days. Dermatitis scoring, ear thickness, and body weight of animals were weekly determined while other parameters were assessed at the termination of the experiment. PTN reduced the ear weight, skin thickness, and the weight and size of thymus glands and spleen in comparison with diseased animals. PTN also reduced the elevated immunoglobulin E (IgE) level and blood inflammatory cells in diseased mice. The histopathological findings showed a decreased epidermal thickness in PTN-treated groups. Moreover, treatment with PTN improved the amount of oxidative stress markers in the skin of the diseased mice. The expressions of IL-4, IL-6, TNF-α, and NF-κB in the skin of diseased mice were also reduced by PTN. This study concludes that PTN ameliorated the symptoms of atopic dermatitis through the reduction of inflammation, oxidative damage, and inflammatory cytokines in the skin of diseased animals. Therefore, PTN must be further investigated for the treatment of AD complications and other inflammatory skin disorders.

Topics: Animals; Cytokines; Dermatitis, Atopic; Mice; Mice, Inbred BALB C; Oxidative Stress; Skin; Stilbenes

Topics: Dermatitis, Atopic; Dermatologic Agents; Humans; Interleukin-33; Keratinocytes; Psoriasis; Receptors, Aryl Hydrocarbon; Resorcinols; Stilbenes

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.

Topics: Cell Differentiation; Cells, Cultured; Dermatitis, Atopic; Filaggrin Proteins; Humans; Interleukins; Intermediate Filament Proteins; Janus Kinases; Keratinocytes; Membrane Proteins; Receptors, Aryl Hydrocarbon; Resorcinols; Signal Transduction; STAT3 Transcription Factor; Stilbenes

Tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for patients with psoriasis and atopic dermatitis, although the biologic target and mechanism of action had been unknown. We demonstrate that the anti-inflammatory properties of tapinarof are mediated through activation of the aryl hydrocarbon receptor (AhR). We show that tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue-human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence. That the anti-inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice. In summary, these studies identify tapinarof as an AhR agonist and confirm that its efficacy is dependent on AhR.

Topics: Administration, Topical; Animals; Basic Helix-Loop-Helix Transcription Factors; Cells, Cultured; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Humans; Inflammation; Mice; Psoriasis; Receptors, Aryl Hydrocarbon; Resorcinols; Skin; Stilbenes

Polydatin(PD) shows anti-allergic inflammatory effect, and this study investigated its underlying mechanisms in in vitro and in vivo models. IgE-mediated passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis (PSA) models were used to confirm PD effect in vivo. Various signaling pathway proteins in mast cell were examined. RT-PCR, ELISA and western blotting were applied when appropriate. Activity of Lyn and Fyn kinases in vitro was measured using the Kinase Enzyme System. PD dose-dependently reduced the pigmentation of Evans blue in the PCA model and decreased the concentration of serum histamine in PSA model, and attenuated the degranulation of mast cells without generating cytotoxicity. PD decreased pro-inflammatory cytokine expression (TNF-α, IL-4, IL-1β, and IL-8). PD directly inhibited activity of Lyn and Syk kinases and down-regulated downstream signaling pathway including MAPK, PI3K/AKT and NF-kB. In addition, PD also targets Nrf2/HO-1 pathway to inhibit mast cell-derived allergic inflammatory reactions. In conclusion, the study demonstrates that PD is a possible therapeutic candidate for allergic inflammatory diseases. It directly inhibited activity of Lyn and Syk kinases and down-regulates the signaling pathway of MAPK, PI3K/AKT and NF-κB, and up-regulates the signaling pathway of Nrf2/HO-1 to inhibit the degranulation of mast cells.

Topics: Anaphylaxis; Animals; Cell Degranulation; Cytokines; Dermatitis, Atopic; Extracellular Signal-Regulated MAP Kinases; Glucosides; Heme Oxygenase-1; Inflammation; Male; MAP Kinase Signaling System; Mast Cells; Membrane Proteins; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Stilbenes

Resveratrol is a polyphenol abundantly found in red grape skin and is effective against antiaging and anti-inflammation associated with immune responses. In this study, we have investigated the effect of resveratrol on skin lesion, high mobility group box (HMGB)1 and inflammation pathway in an atopic dermatitis (AD) mouse model. AD-like lesion was induced by the application of house dust mite extract to the dorsal skin of NC/Nga mouse. After AD induction, resveratrol (20 mg/kg, p.o.) was administered daily for 2 weeks. We evaluated dermatitis severity, histopathological changes, serum levels of T helper (Th) cytokines (interferon (IFN)γ, interleukin (IL)-4) and changes in protein expression by Western blotting for HMGB1, receptor for advanced glycation end products (RAGE), toll like receptor (TLR)4, nuclear factor (NF)κB, phosphatidylinositide 3-kinase (PI3K), extracellular signal-regulated kinase (ERK)1/2, cyclooxygenase (COX)2, tumor necrosis factor (TNF)α, IL-1β, IL-2Rα and other inflammatory markers in the skin of AD mice. Treatment of resveratrol inhibited the development of the AD-like skin lesions. Histological analysis showed that resveratrol inhibited hypertrophy, intracellular edema, mast cells and infiltration of inflammatory cells. Furthermore, resveratrol treatment down-regulated HMGB1, RAGE, p-NFκB, p-PI3K, p-ERK1/2, COX2, TNFα, IL-1β, IL-2Rα, IFNγ and IL-4. Considering all these findings together, the HMGB1 pathway might be a potential therapeutic target in skin inflammation, and resveratrol treatment could have beneficial effects on AD by modulating the HMGB1 protein expression.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Female; HMGB1 Protein; Mice, Inbred Strains; Pyroglyphidae; Resveratrol; Severity of Illness Index; Signal Transduction; Skin; Stilbenes; Th1 Cells; Th2 Cells

Topics: Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Female; Humans; Male; Resorcinols; Stilbenes