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(1) Background: Human keratinocytes and murine skin express various cytochrome P450 enzymes. These include cytochrome P450 3A4, which may participate in the metabolism of cytochrome P450 3A4 substrate drugs. Desoximetasone, a topical corticosteroid and cytochrome P450 3A4 substrate, is used to treat skin conditions such as skin allergies, atopic dermatitis, and psoriasis. In this study, we aimed to investigate the anti-psoriatic effect of a low dose of desoximetasone by inhibiting cytochrome P450 3A4 metabolism in the epidermis. (2) Methods: Psoriasis-like skin was induced in BALB/c mice via the topical administration of imiquimod. The mice were then topically treated with 0.01–0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient microemulsion, 0.25% commercial desoximetasone ointment, or 0.5 mg/gm clobetasol ointment. (3) Results: The topical application of 0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation restored the imiquimod-induced skin barrier disruption and resulted in fewer severe clinical and pathological features compared with the treatments with 0.25% commercial desoximetasone ointment and 0.5 mg/gm clobetasol ointment. (4) Conclusions: The cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation improved and prolonged the therapeutic effect of cytochrome P450 3A4 substrate drugs and may be a promising approach for psoriasis treatment. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) is particularly produced in the skin, where it participates in the regulation of inflammation, pruritus, cytoprotection, scarring, and angiogenesis. In this study, we compared the effects of dexamethasone (Dex) with two H2S-releasing Dex derivatives in a murine model of atopic dermatitis (AD) induced by topical application of 2,4-dinitrochlorobenzene (DNCB). After sensitization with DNCB, the animals were topically treated for five consecutive days with either the H2S-releasing compounds 4-hydroxy-thiobenzamide (TBZ) and 5-(p-hydroxyphenyl)-1,2-dithione-3-thione (ADT-OH), Dex, or the derivatives Dex-TBZ or Dex-ADT. Topical treatment with equimolar doses of either Dex, Dex-TBZ, or Dex-ADT resulted in similar reductions in dermatitis score, scratching behavior, edema, eosinophilia, splenomegaly, and histological changes. In contrast with Dex, the H2S-releasing derivatives prevented IL-4 elevation and oxidative modification of skin proteins. On an equimolar dose basis, Dex-TBZ, but not Dex-ADT, promoted the elevation of endogenous H2S production and GPx activity. Neither Dex-TBZ nor Dex-ADT decreased GR activity or caused hyperglycemia, as observed with Dex treatment. We conclude that the presence of H2S-releasing moieties in the Dex structure does not interfere with the anti-inflammatory effects of this corticosteroid and adds beneficial therapeutical actions to the parent compound. [ABSTRACT FROM AUTHOR]

The topical route is the most appropriate route for the targeted delivery of drugs to skin tissues for the treatment of local skin diseases; however, the stratum corneum (SC), the foremost layer of the skin, acts as a major barrier. Numerous passive and active drug delivery techniques have been exploited to overcome this barrier; however, these modalities are associated with several detrimental effects which restrict their clinical applicability. Alternatively, nanotechnology-aided interventions have been extensively investigated for the topical administration of a wide range of therapeutics. In this review, we have mainly focused on the biopharmaceutical significance of polymeric nanoparticles (PNPs) (made from natural polymers) for the treatment of various topical skin diseases such as psoriasis, atopic dermatitis (AD), skin infection, skin cancer, acute-to-chronic wounds, and acne. The encapsulation of drug(s) into the inner core or adsorption onto the shell of PNPs has shown a marked improvement in their physicochemical properties, avoiding premature degradation and controlling the release kinetics, permeation through the SC, and retention in the skin layers. Furthermore, functionalization techniques such as PEGylation, conjugation with targeting ligand, and pH/thermo-responsiveness have shown further success in optimizing the therapeutic efficacy of PNPs for the treatment of skin diseases. Despite enormous progress in the development of PNPs, their clinical translation is still lacking, which could be a potential future perspective for researchers working in this field. [ABSTRACT FROM AUTHOR]

Named after the two-faced Roman god of doorways, Janus kinases (JAKs) represent a class of tyrosine kinases. The JAK signaling pathway is pivotal for the downstream signaling of inflammatory cytokines, including interleukins, interferons, and multiple growth factors. This article provides an overview of the JAK pathway and signaling, its significance in immune-mediated dermatologic diseases and the development of a targeted, localized option of a selective JAK inhibitor, ruxolitinib cream. In the early 1990s, various discovery and clinical development programs were initiated to explore pharmaceutical inhibition of the JAK-STAT pathway. Incyte Corporation launched a strategy to identify molecules suitable for both topical as well as oral delivery. Ruxolitinib was designed as a molecule with low nanomolar potency selective for JAK1 and 2 enzymes, but without significant inhibition of non-JAK kinases, as well as physicochemical properties for both topical and oral administration. An oil-in-water emulsified ruxolitinib cream formulation was developed for topical application and was studied in multiple immune-mediated dermatologic diseases including psoriasis, alopecia areata, atopic dermatitis and vitiligo. Ruxolitinib cream represents a novel, JAK1/2 selective therapy that can be delivered directly to the skin to treat a number of cytokine-driven, inflammatory dermatoses. [ABSTRACT FROM AUTHOR]