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- Materials and methods
Atopic dermatitis (AD) is a chronic, relapsing and intensely pruritic inflammatory skin disease in result of a complex interplay of genetic, immunologic and environmental factors.[1-3] The disease occurs most frequently in infancy or early childhood and may persist throughout life in up to 40–60% of the cases. AD causes substantial physical and psychological discomfort for the patients and the affected families and may have considerable negative impact on life quality.
The management of AD requires efficient control of the flares by treatment of the acute inflammatory symptoms along with restoration of the skin barrier homeostasis and avoidance of the relevant triggering or disease-aggravating factors. Topical steroids and immunomodulators are first-line treatment of the disease flares, whereas the long-term management is based on the use of emollients that aim to improve skin hydration, maintain the barrier integrity, relieve pruritus and prevent new flares.[6-8] Although independent lines of research suggest that the use of emollients may result in enhanced therapeutic responses and improved outcomes, so far there has been limited evidenced-based proof concerning the stand-alone efficacy of emollients in acute stage of disease.[5, 6, 9] Therefore, in the present study, we investigated the effects of an o/w formulation containing licochalcone A (Glycyrrhiza Inflata root extract), decanediol (decylene glycol), menthoxypropanediol and ω-6-fatty acids with regard to reduction of the lesional severity, pruritus relief, improvement of the skin barrier function and reduction in pathogenic bacterial colonization in AD patients with mild to moderately severe disease flare.
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- Materials and methods
In the present study, we have shown that the stand-alone application of an emollient, tailored to target inflammation, pruritus, compromised barrier function and pathogenic bacterial colonization is an efficient and safe approach for improvement of mild to moderately severe AD flares. As 1% HC, the 1-week twice daily application of AC lead to significant reduction in the severity of signs and symptoms, improvement of the skin barrier function and decrease in lesional skin S.aureus colonization density. There were no significant differences with respect to the time frame and the scale of exerted effects between the study arms; in addition to the efficacy of AC, the findings for comparable outcomes between the emollient (AC-AL) and hydrocortisone (HC-AL) arm at the end of the study suggest the steroid-sparing potential of the emollient regimen.
The efficacy of licochalcone A for improvement of the clinical manifestations of AD has been initially suggested by the findings of a controlled, randomized, investigator-blinded study in children with mild to moderately severe disease that showed significant reduction in SCORAD and lack of significant differences in the outcomes after 6-week twice daily application of a licochalcone A-based emollient compared to 1% HC.
Licochalcone A is a reversely constructed chalcone specific for the Xynjiang licorice root Glycyrrhiza inflata, used in cosmetic formulations due to its potent anti-inflammatory and antioxidative properties.[19-21] Experimental studies have shown that licochalcone A-rich extracts from G. inflata and synthetic licochalcone A suppress the production of pro-inflammatory mediators and cytokines such as PGE2, LTB4, IL-6 and TNF-α in in vitro systems relevant to the skin such as dermal fibroblasts, granulocytes, dendritic cells and human skin equivalents.[22-24] The in vitro findings have been further confirmed by in vivo studies showing the efficacy of licochalcone A-containing formulations for reducing experimentally induced erythema, improvement of the inflammatory signs in patients with rosacea and recently – in mild to moderately severe inflammatory forms of acne.[24-26] The findings of the present study extend these observations and provide new evidence for the anti-inflammatory effects of licochalcone A in mild to moderately severe AD, on the basis of clinical assessment and non-invasive skin bioengineering methods.
Pruritus is a major diagnostic criterion and a cardinal symptom of AD.[10, 27, 28] Though the first-line anti-inflammatory agents such as topical steroids and calcineurin inhibitors are known to induce short-term improvement, the achievement of lasting relief is a challenge and a most important goal in disease management.[29, 30] The pathogenesis of itch related to AD involves numerous factors within the skin, nervous system and the environment and recent advances indicate a critical role for different thermosensitive members of the transient receptor potential (TRP) ion channels superfamily in the transmission and modulation of itch.[31-34] Independent lines of research provide evidence that both the generation and the alleviation of itch is temperature-dependent. Skin cooling and topical application of substances that induce a cooling sensation upon contact with the skin and mucosae such as menthol, eucalyptol or icilin have been shown to mitigate experimentally induced and disease-related itch.[34-37] The cooling sensation has been further shown to be mediated by the activation of TRPM8, a thermosensitive calcium-permeable channel expressed in the sensory neurons and activated by temperatures ≤28°C as well as cooling agents suggesting that TRPM8 may be a novel pharmacological target for the management of itch.[32, 34, 38-41] The findings of the study are consistent with this concept and provide initial in vivo evidence for pruritus relief in result of the use of an emollient containing methoxypropanediol, a TRPM8 agonist, in atopic skin.
A strong line of publications shows the positive correlation between S.aureus colonization density and AD severity.[42-44] Atopic skin provides a favourable environment for increased S.aureus adherence and proliferation attributed to distinct, interrelated pathomechanisms including compromised barrier integrity, altered sphingolipid metabolism[45-49] and expression of antimicrobial peptides, upregulation of extracellular matrix adhesins[51, 52] as well as enhanced pathogen binding to areas of Th2-mediated inflammation.[44, 53] Earlier publications indicate that 30–60% of the S.aureus strains isolated from AD patients produce exotoxins with superantigen properties that exert potent disease-promoting effects while at the same time, contribute to induction of corticosteroid resistance and alter the therapeutic responses.[54-57]
In view of the relevance of S.aureus colonization for disease exacerbation and chronicity, the reduction in the bacterial density in result of emollient use is an important finding of our study. In addition to direct S.aureus targeting by decanediol, the active antimicrobial component of the AC formulation, the observed effects may have been further enhanced by the improvement of the compromised barrier conditions through reduction in the lesional severity, decrease in TEWL and increase in skin hydration.
In the present investigation, HC was used as a reference for the effects exerted by the o/w formulation with respect to clinical outcomes, barrier function and pathogenic bacterial colonization. Independently of the study design, the formulation is in a strict sense an emollient and therefore, not meant as alternative to first-line topical medications intended to treat AD. The presented results, however, provide proof-of-principle that the stand-alone use of emollients may offer benefit from a clinical, laboratory and patient's perspective and exert a steroid-sparing effect that would equal the amount of used HC.