Comparison Between Topical N-acetyl Cysteine (NAC) in Cold Cream Versus Cold Cream in Mild and Moderate Atopic Dermatitis: Clinical and Bacteriological Evaluation. A Randomized Control Trial.

Atopic Dermatitis (AD)

N-acetyl cystiene, Atopic dermatitis

Atopic dermatitis (AD), or atopic eczema, is a chronic relapsing, inflammatory skin disease, characterized by intense pruritus that leads to considerable burden on patients' quality of life (Sidbury et al., 2023). The dramatic rise of AD prevalence in the past half century is well documented, with prevalence reaching 15-30% of children and 2-10% of adults worldwide. Onset of the disease usually starts in childhood and although most cases resolve by adolescence, a fraction remains afflicted in adulthoodThe exact etiopathogenisis of AD is not well understood, being a complex interplay between genetic, environmental and immunological factors (Serra-Baldrich et al., 2017). Cutaneous flora imbalance in AD is well established. In particular, Staph aureus colonization is found in the vast majority of AD patients, especially in the sweat gland ducts (Gonzalez et al., 2017). Some studies found that the prevalence of Staph aureus colonization exceeds 90% of AD patients in comparison to most healthy people. In Staph. aureus- colonized AD patients, the Staph. aureus density in lesional skin was found to be more than in non-lesional skin. Recently, a temporal relationship between Staph. aureus density and clinical severity of AD was found, strongly implicating Staph. aureus in disease pathogenesis (Di Domenico et al., 2019; Ogonowska et al., 2021). Atopic dermatitis-derived Staphylococcus. epidermidis strains elicit higher inflammatory response than healthy strains.it was found that Staph. epidermidis in AD triggers inflammation by activating NF-kappa B, induces pro-inflammatory cytokines, downregulates skin barrier molecules like filaggrin and it is more prevalent in severe cases(Ochlich et al., 2023). After antimicrobial therapies targeting reduction of Staphylococcus colonization, clinical symptoms significantly decline along with resettling of diverse microflora (Brüssow, 2016). However, the propensity of Staph. aureus and Staph. epidermidis to form protective biofilms and rapid emergence of antibiotic resistance pose grave concern and prompt the search for other antimicrobial agents with less risk of resistance such as non-antibiotic antimicrobial agents and phototherapy (Brockow et al., 1999; Gonzalez et al., 2017; Man et al., 2017). Despite advances in systemic therapy for AD, topical therapies remain the mainstay of treatment due to their proven efficacy to alleviate inflammation and pruritus and generally favorable safety profile. They include emollients,corticosteroids, calcineurin inhibitors and antimicrobials (Sidbury et al., 2023). N-acetyl cysteine (NAC) is a widely used drug in human clinical practices. It has been systemically used in the treatment of acetaminophen toxicity and as a mucolytic agent in the treatment of lower respiratory tract diseases, and its uses is recently increasing. (Janeczek et al., 2019). Regarding dermatological applications; Efficacy of N-acetyl cysteine was shown in excoriation disorder, onychophagia disorder, trichotillomania, acne vulgaris, Type I lamellar ichthyosis, bullous morphea, systemic sclerosis, toxic epidermal necrolysis, atopic dermatitis, xeroderma pigmentosum, and pseudoporphyria. Studies also show benefits in wound healing and photoprotection (Janeczek et al., 2019). N-acetyl cysteine also has antioxidant, cytoprotective, anti-inflammatory and antimicrobial properties. Oxidative stress contributes to barrier dysfunction in AD. NAC is a precursor of glutathione, a potent antioxidant which improves the barrier function. NAC also modulates cytokine production: tumor necrosis factor-alpha (TNF-α) and interleukins (IL-6 and IL-1β) by suppressing the activity of nuclear factor kappa B (NF-κB), potentially reducing the inflammatory response associated with Staph. aureus colonization. (Tenório et al., 2021) In addition, the published literature shows that NAC has an adverse effect on biofilm formation and impedes its formation at various stages. N-acetyl cysteine, as an acidic compound, applied at high concentrations, was able to penetrate the biofilm and bacterial membrane and increase the intracellular oxidative status and halt protein synthesis, in this way killing the bacterial cells (Li et al., 2020).Regarding skin hydration; NAC solution (20 w/v%) was applied to the forearm skin twice a day for 4 weeks resulted in increased skin hydration in 9/11 AD patients and decreased TEWL in 9/10 AD patients (Nakai et al., 2015). N-acetyl cysteine restored the expression of some cell adhesion molecules that contribute to forming the skin barrier in a mouse model of AD by reducing oxidative stress. Therefore, the topical application of NAC may have increased skin hydration and decreased Trans-epidermal water loss (TEWL) by strengthening the function of this barrier (Nakai et al., 2017).

Despite NAC relevant therapeutic potential, in several experimental studies, its effectiveness in clinical trials, addressing different pathological conditions, is still limited. Only one cohort study was done on humans using 20% NAC solution but 10% NAC in cold cream was the maximum concentration feasible for manufacture for our study. We first conducted a pilot study on 7 patients and it showed clinical improvement together with reduction in the colony count of Staph. aureus, therefore we decided to test this concentration on a larger scale. To the best of our knowledge, this is the first RCT conducted on atopic dermatitis patients using 10% NAC in cold cream.

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