sirolimus and Dermatitis--Atopic

The field of pediatric dermatology treatment has been rich in new developments. Several recent therapeutic advances in pediatric dermatology have been made. This review will focus on critical approach to the new treatments for several entities encountered in pediatric dermatology. The use of biologics and small molecules in children with atopic dermatitis and psoriasis, exciting advances in the use of propranolol and other beta-blockers for the treatment of infantile hemangiomas, the use of sirolimus for vascular anomalies will be discussed.

Topics: Adrenergic beta-Antagonists; Biological Products; Child; Dermatitis, Atopic; Hemangioma; Humans; Phosphodiesterase 4 Inhibitors; Psoriasis; Sirolimus; Skin Diseases

The immunomodulatory macrolactams provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Tacrolimus (FK506), as well as the newer ascomycin derivative ASM 981 (pimecrolimus), penetrate the inflamed epidermis and are suitable for topical therapy. Both substances inhibit the transcription of proinflammatory cytokine genes such as interleukin 2, which are dependent on the nuclear factor NF-AT. They block the catalytic function of calcineurin, which leads to the inhibition of the transport of the cytoplasmic component of NF-AT to the cell nucleus. Multicenter, randomized, double-blind clinical trials with topical formulations have shown the efficacy of both substances in moderate to severe atopic dermatitis. A review is presented of the biochemical and cell biologic properties, mode of action, pharmacokinetic data, side effects, results of the clinical trials, and further indications for tacrolimus and ASM 981, along with an overview of the related substances cyclosporine and sirolimus (rapamycin).

Topics: Administration, Topical; Clinical Trials as Topic; Cyclosporine; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Inflammation; Sirolimus; Skin Diseases; Tacrolimus

Topics: Animals; Anti-Bacterial Agents; Carrier Proteins; Cyclosporine; Dermatitis, Atopic; Dermatitis, Contact; Disease Models, Animal; Guinea Pigs; Immunosuppressive Agents; Mice; Polyenes; Receptors, Drug; Receptors, Immunologic; Sirolimus; Swine; Tacrolimus; Tacrolimus Binding Proteins

Interleukin (IL)-13 plays a key role in the pathogenesis of atopic dermatitis (AD). Our preliminary study demonstrated that forced expression of miR-143 could block IL-13-induced down-regulation of epidermal barrier related proteins in epidermal keratinocytes. As previous studies suggested that miR-143 expression was regulated by mammalian target of rapamycin (mTOR) signaling pathway, we investigated the mechanism of mTOR signaling pathway in the epidermal barrier dysfunction of AD. The HaCaT cells were stimulated by IL-13 and subsequently treated with rapamycin. The expression levels of miR-143, IL-13 receptor α1 (IL-13Rα1), p-mTOR, p-S6K1, p-Akt, and epidermal barrier related proteins were analyzed through RT-qPCR and/or western blotting. The current study showed that IL-13 increased the expression levels of p-mTOR, p-S6K1, and p-Akt, and that rapamycin blocked IL-13-induced down-regulation of miR-143, suppressed the IL-13Rα1 expression and up-regulated the expressions of filaggrin, loricrin, and involucrin in HaCaT cells. This study proposed that IL-13 could activate the mTOR signaling pathway, and confirmed the vital role of mTOR-miR-143 signaling axis in the pathogenesis of AD. It provided solid evidences regarding rapamycin as a potential effective therapeutic option in the management of AD.

Topics: Dermatitis, Atopic; Filaggrin Proteins; HaCaT Cells; Humans; Interleukin-13; Interleukin-13 Receptor alpha1 Subunit; Keratinocytes; Membrane Proteins; MicroRNAs; Protein Precursors; S100 Proteins; Signal Transduction; Sirolimus; Skin; TOR Serine-Threonine Kinases; Up-Regulation

Rapamycin (RPM) and mycophenolic acid (MPA) are immunosuppressive drugs approved for use in preventing transplant rejection. These drugs have also been used in the field of dermatology as glucocorticoid sparing agents for autoimmune and inflammatory disorders such as atopic dermatitis (AD). The aim of this study was to investigate the therapeutic effect of topically applied RPM and/or MPA on AD-like skin lesions in NC/Nga mice. RPM (0.04% - 4%), MPA (0.2% - 5%), and formulations of both agents at various ratios were administrated topically to NC/Nga mice with 2-chloro-1,3,5-trinitrobenzene (TNCB)-induced AD-like skin lesions. The therapeutic effects of topical RPM, MPA, and the mixed formulations in TNCB-treated NC/Nga mice were assessed by measuring skin severity scores, ear thickness, and histological changes in the lesioned skin including mast cell count and total serum IgE levels. Expression of interleukin (IL)-4, and interferon (IFN)-γ was also assessed. Topical 4% RPM and/or 1% MPA treatment significantly improved clinical signs of AD such as erythema, edema, excoriation, and dryness on day 29 (P<0.05). In addition, 4% RPM, 1% MPA, and the mixed formulations significantly decreased epidermal thickening, dermal edema, and cellular infiltration into the dermis compared with the vehicle. RPM (4%) and/or MPA (1%) significantly reduced the expression of IL-4 and IFN-γ mRNA and protein levels compared with the vehicle (P<0.05). No significant change in the levels of total serum IgE was induced by topical 4% RPM and/or 1% MPA. The present results demonstrated that topical 4% RPM and/or 1% MPA improved TNCB-induced AD-like lesions of NC/Nga mice by suppressing expression of Th2-related cytokines (IL-4) and Th1-related cytokines (IFN-γ). These findings suggest that RPM and/or MPA may be promising topical therapeutic candidates for the treatment of AD.

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Edema; Immunoglobulin E; Immunosuppressive Agents; Interferon-gamma; Interleukin-1; Mast Cells; Mice; Mice, Inbred Strains; Mycophenolic Acid; Sirolimus; Skin; Trinitrobenzenes

Atopic dermatitis (AD), a chronic inflammatory skin disease characterized by relapsing eczema and intense prurigo, requires effective and safe pharmacological therapy. Recently, rapamycin, an mTOR (mammalian target of rapamycin) inhibitor, has been reported to play a critical role in immune responses and has emerged as an effective immunosuppressive drug. In this study, we assessed whether inhibition of mTOR signalling could suppress dermatitis in mice. Rapamycin was topically applied to inflamed skin in a murine AD model that was developed by repeated topical application of Dermatophagoides farina body (Dfb) extract antigen twice weekly for 7 weeks in NC/Nga mice. The efficacy of topical rapamycin treatment was evaluated immunologically and serologically. Topical application of rapamycin reduced inflammatory cell infiltration in the dermis, alleviated the increase of serum IgE levels and resulted in a significant reduction in clinical skin condition score and marked improvement of histological findings. In addition, increased mTOR phosphorylation in the lesional skin was observed in our murine AD model. Topical application of rapamycin ointment inhibited Dfb antigen-induced dermatitis in NC/Nga mice, promising a new therapy for atopic dermatitis.

Topics: Administration, Topical; Animals; Cytokines; Dermatitis, Atopic; Dermatophagoides farinae; Disease Models, Animal; Female; Immunosuppressive Agents; Mice; Mice, Mutant Strains; Ointments; Phosphorylation; Signal Transduction; Sirolimus; Skin; Tissue Extracts; TOR Serine-Threonine Kinases

Topics: Dermatitis, Atopic; Dermatologic Agents; Everolimus; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Medication Adherence; Sirolimus; Treatment Failure; Treatment Outcome

Patients with severe atopic dermatitis (AD) often require treatment with oral immunosuppressive drugs. Everolimus is a rapamycin-derived macrolide with immunosuppressive and antiproliferative effects. Everolimus demonstrated efficacy not only in the prophylaxis of organ rejection in kidney transplant patients, but also in decreasing disease activity in psoriasis patients.. To evaluate whether everolimus is an effective treatment in patients with severe AD.. Two patients with severe AD were treated with everolimus in combination with low-dose cyclosporin A (CsA) or prednisone. During treatment, a disease activity and safety laboratory examination was performed.. Everolimus either in combination with prednisone or with CsA did not result in improvement of disease activity in two patients with severe AD.. Everolimus does not seem to be an effective treatment in these two AD patients, either in combination with prednisone or with CsA.

Topics: Cyclosporine; Dermatitis, Atopic; Dermatologic Agents; Drug Therapy, Combination; Everolimus; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Middle Aged; Severity of Illness Index; Sirolimus; Treatment Failure

Activation and skin-selective homing of T cells and effector functions in the skin represent sequential events in the pathogenesis of atopic dermatitis and allergic contact dermatitis.. T cell-mediated keratinocyte apoptosis plays a key pathogenetic role in the formation of eczematous dermatitis. IFN-gamma released from activated T cells upregulates Fas on ke-ratinocytes, which renders them susceptible to apoptosis. The lethal hit is given to keratinocytes by means of Fas ligand expressed on the T-cell surface or released to the inflammatory microenvironment. We sought to investigate whether drugs used for the treatment of eczematous disorders interfere with this pathogenic pathway.. T cell-mediated, Fas-induced keratinocyte apoptosis in a keratinocyte-T cell coculture system serves as an in vitro model of eczematous dermatitis. We tested, in this model, whether immunomodulatory agents (dexamethasone, cyclosporine A, rapamycine, tacrolimus/FK506, intravenous immunoglobulin [IVIG], and theophylline) are able to inhibit apoptosis of keratinocytes. Additionally, skin biopsy specimens from patients with untreated and successfully treated eczematous dermatitis were evaluated for keratinocyte apoptosis.. Dexamethasone, cyclosporine A, FK506, rapamycine, and IVIG are inhibitors of keratinocyte apoptosis induced by activated T cells. This effect is mediated by 2 major mechanisms directed on T cells or keratinocytes. T-cell activation was mainly inhibited by dexamethasone, FK506, cyclosporine A, and rapamycine. Interestingly, high-dose dexamethasone and IVIG directly inhibited Fas-mediated keratinocyte apoptosis. In vivo keratinocyte apoptosis was significantly reduced after successful topical treatment of eczematous lesions.. These results demonstrate mechanisms of action of current treatment approaches and provide a future for more focused therapeutic applications.

Topics: Acute Disease; Apoptosis; Cells, Cultured; Cyclosporine; Dermatitis, Allergic Contact; Dermatitis, Atopic; Dexamethasone; fas Receptor; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Interleukin-12; Keratinocytes; Sirolimus; T-Lymphocytes; Tacrolimus; Th1 Cells; Theophylline

The immunosuppressive macrolides are a novel class of antiinflammatory substances, which could supplant glucocorticosteroids for the topical treatment of some chronic inflammatory skin diseases. Cyclosporine A (CyA), well known from transplantation medicine for years, is licensed in Germany for oral treatment of psoriasis and atopic dermatitis but is not suitable for topical therapy. Tacrolimus (FK506) penetrates the inflamed epidermis and is regarded as the key immunosuppressive macrolide. Clinical trials have demonstrated the efficacy of FK506 ointment for atopic dermatitis, many case reports have been published regarding other inflammatory skin diseases. The ascomycin derivative ASM 981 has many of the properties of FK506 but less data is available at present. Sirolimus (Rapamycin) is structurally related to FK506 but has other biological effects since its molecular actions involve different biochemical pathways. A review of the biochemical and cellular properties, mode of action, therapeutic efficacy and unwanted side effects, as well as data from clinical trials and status of licensing, is given for the respective drugs.

Topics: Administration, Topical; Clinical Trials as Topic; Cyclosporine; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Psoriasis; Sirolimus; Tacrolimus