AD is uncomfortable and distressing to patients because of the associated pruritus and unsightly lesions [16]. Chil- dren with AD may suffer from lack of sleep, irritability, day- time tiredness, emotional stress, lowered self-esteem, and psychological disturbance [17,18]. The disruption of school, family, and social interactions can severely impair the qual- ity of life and extends beyond the child [17,19-21]. Parents may experience guilt, frustration, resentment, exhaustion, and helplessness due to their child’s condition [8]. There are also considerable economic costs associated with caring for children with AD [8].

AD most often presents in infancy or early childhood [1,3]. Approximately 60% of children with AD manifest the disease by the first year of life and an additional 30% before the age of 5 years [1, 3, 22]. In infants, the eruption often affects the face and scalp, although the extensor surfaces of the extremities and the trunk may also be affected [3, 23]. In older children and adolescents, the neck and antecubital and popliteal fossae usually display the eruption [3, 23].

The diagnosis of AD is predominantly clinical, based on a constellation of clinical features. Firm criteria to define AD were first established by Hanifin and Rajka [1, 24]. The UK working diagnostic criteria are also concise and practical [25-27].

AD involves defective cell-mediated immunity related, in part, to an imbalance in two subsets of CD4-T cells that cre- ates a predominance of T-memory cells in the T-helper 2 pathways and preferential apoptosis of interferon-gamma producing T-helper 1 memory and effector T-cells [3-5]. T- Helper 2 cells express a set of cytokines (interleukin-4, -5, - 6, -10, and -13) [4, 28]. These cytokines stimulate the prolif- eration and differentiation of B-lymphocytes, upregulate the expression of adhesion molecules on endothelial cells, and contribute to the hypereosinophilia, high serum IgE levels, sustained cutaneous inflammation, histamine release, and pruritus characteristic of AD [16]. Recently, we demon- strated that AD involves many complex immune pathways in addition to aberration of cell-mediated immunity [29].

THE PATHOGENESIS OF DRY SKIN

Xerosis or dry skin results from reduced amount of cera- mides in the skin with enhanced TEWL Fig. (1). It is seen in 67 to 98% of patients with AD [24, 30]. Xerosis predisposes to the development of microfissures and cracks in the epithe- lium which favor the entry of allergens and microorganisms [12].

The pathogenesis of AD involves complex interactions between susceptible genes, immunological factors, skin bar- rier defects, infections, neuroendocrine factors, and envi- ronmental factors [1] Fig. (2). There is a strong genetic pre- disposition, as evidenced by the familial nature of the disease and the high concordance in monozygotic twins [1, 31]. It has been shown that loss-of-function mutations in the filag- grin (filament-aggregating protein) (FLG) gene predispose to AD [32-35]. Five FLG null mutations, namely R501X, 2282del4, R2447X, S2554X, and S2889X, are some of the more popular mutations identified in Caucasian and Japanese populations [36]

Impairment of the barrier function of the skin is an im- portant etiologic factor in the pathogenesis of AD [1]. FLG, an epidermal barrier protein, plays an important role in the barrier function of the skin [37]. The protein is present in the granular layers of the epidermis. The keratohyalin granules in the granular layers are predominantly composed of pro- filaggrin [38] Fig. (1). FLG aggregates the keratin cytoskele- ton system to form a dense protein-lipid matrix that is cross- linked by transglutaminases to form a cornified cell envelope [37, 38]. The latter prevents epidermal water loss and im- pedes the entry of allergens, infectious agents, and chemicals [37]. It is believed that defective epidermal function is re- lated to the down-regulation of the FLG gene and reduced ceramide levels [39]. FLG has an important function in epi- dermal differentiation and barrier function [40-43]. Null mu- tations within the FLG gene cause ichthyosis vulgaris and are major risk factors for AD. Recent findings have shown that the affected skin of atopic individuals is deficient in natural moisturizing factors (derived from deiminated filag- grin peptides filaggrin) or ceramides (a family of lipid mole- cules, composed of sphingosine and a fatty acid, found in high concentrations within the cell membrane of cells in the stratum corneum) [44], .

A reduced content of ceramides has been noted in both normal and affected skin of patients with AD [44-46]. The reduction in ceramides may result from increased sphingo- myelin deacylace activity and reduced production of ceramides by keratinocytes [4]. Ceramides serve as important water-holding molecules in the extracellular space in the horny layer [6]. Ceramides link the protein-rich corneocytes into a waterproof barrier that is capable of protecting the underlying skin tissues and regulating body homeostasis. A deficiency in ceramides results in enhanced transepidermal water loss (TEWL), dry skin, and increased permeability to environmental irritants and allergens [4]. Increased TEWL is observed in patients with AD [47, 48]. In addition, keratino- cyte-derived antimicrobial peptides known as cathelicidins and þ-defensins are deficient in the skin of patients with AD [47, 49]. These peptides help in the host defense against bac- teria, viruses, and fungi.

OPTIMAL SKIN CARE: RELEVANCE OF CERA- MIDES AND PSEUDOCERAMIDES

AD is frustrating to both patients and caregivers. The pruritus can be intractable and the disease has important physical and psychological implications. Because of associsated emotional stress and sleep disruption, the impact on the quality of life of patients and families can be significant [1,18, 50]. Successful treatment requires a holistic approach that consists of avoidance of triggering factors, optimal skin care, pharmacotherapy during acute exacerbations, and edu- cation of patients/caregivers.Although there is no cure, control is possible in most patients with  optimal skin care, pharmacotherapy, and adherence to preventive measures [51, 52]. Pharmacotherapy usually consists of topi- cal application of corticosteroids or calcineurin  inhibitors [1].

Dry skin is more prone to itch and chapping and hence secondary infection and subsequent perpetuation of AD. Hy- dration of the skin increases drug penetration as hydration causes swelling of the stratum corneum rendering it more permeable to drug molecules. The key to management of AD and dry skin conditions, especially in between episodes of flare ups, is the frequent use of an appropriate moisturizer [1]. Hydration of the skin helps to improve the dryness, reduce the pruritus, and restore the disturbed skin’s barrier function. It is of paramount importance both in the preven- tion and management of patients with AD [1, 39]. In the brick-and-mortar hypothesis, the stratum corneum, the out- ermost layer of the epidermis, normally consists of fully dif- ferentiated corneocytes surrounded by a lipid-rich matrix containing cholesterol, free fatty acids, and ceramide; the structure of this matrix closely resembles that of bricks and mortar in a wall. Three classes of lipid molecules account for over 85% of the dry mass of stratum corneum matrix: cera- mides (50%), fatty acids (10-20%), and cholesterol (25%) In AD, null mutation in the FLG gene results in abnormal lipid metabolism and a deficiency of ceramide that leads to in- creased TEWL [7, 34, 53, 54].

Regular topical application of a moisturizer is the corner- stone in the management of patients with AD. A moisturizer or emollient should be applied within 3 minutes of a bath to prevent evaporation of water and to keep the skin soft and flexible [1, 55]. This “soak and seal” method helps to im- prove the integrity of the skin barrier and prevents the pene- tration by bacteria, irritants and allergens. Bathing without the use of moisturizer may compromise skin hydration [56].

The use of moisturizers helps the skin maintain a defen- sive barrier effect, which is defective in patients with AD [57]. AD is associated with dry skin and skin hydration cor- relates with disease severity. It is thus sensible to encourage patients to use moisturizers regularly [52]. The skin condi- tion may improve significantly with the liberal use of mois- turizers such that the use of topical corticosteroids or cal- cineurin inhibitors could be minimized.

A number of topical preparations are available in the market. The actual ingredients in most of  these products are a commercial secret of individual pharmaceutical companies. The commonly used and inexpensive moisturizers include aqueous cream, emulsifying ointment, and urea cream. Aqueous cream B.P. contains emulsifying wax (9%), white soft paraffin (15%), liquid paraffin 6%, phenoxyethanol 1%, and purified water to make up to 100%. It is an oil-in-water emulsion with phenoxyethanol as the preservative. Emulsify- ing ointment B.P. contains white soft paraffin 50%, emulsi- fying wax 30%, and liquid paraffin 20%. The type of mois- turizer or emollient should be tailored to the individual skin condition as well as the child’s needs and preferences [58, 59]. The major hindrance to the efficacy of a moisturizer is the patient’s perception as to what an ideal moisturizer should be [60]. This perception varies from person to person. The physician or health care provider can guide the patient to choose the most appropriate formulation for optimal compli- ance.

Patients should be given practical advice in their daily skin care. In areas rich with sebaceous glands such as the face, formulations should contain less oil than on other body areas [58]. Lotions, which have a high water and low oil content, can worsen xerosis via evaporation and should therefore be avoided. A dye-free, fragrance-free moisturizer should be used [39]. Frequent applications of moisturizers throughout the day help to maintain a high level of hydration in the stratum corneum [1].

Moisturizers containing urea, alpha-hydroxy fatty acids, glycyrrhetinic acids, hyaluronic acid or ceramides have been shown to improve the integrity of stratum corneum [53, 55, 61-63]. Ceramides and pseudoceramides have been studied and added to commercial moisturizers to mimic natural skin moisturizing factors. Proper moisturizer therapy can reduce the frequency of flares and reduce the demand of topical corticosteroids or topical calcineurin inhibitors in a number of studies [13, 64-66]. It has been shown that ceramide- dominant emollients influence on both transepidermal water loss and expression of antimicrobial peptides in patients with AD [47]. The use of ceramide-dominant emollients is asso- ciated with restoration of permeability barrier function with concomitant improvement of antimicrobial defense in pa- tients with AD. Frankel et al. evaluated the short-term effec- tiveness and appeal of a ceramide-hyaluronic acid emollient foam as compared to pimecrolimus cream 1% in the treat- ment of AD within a wide age group of subjects with active AD at baseline [64]. In this study, both pimecrolimus cream and the ceramide-hyaluronic acid emollient foam exhibited efficacy in patients with mild-to-moderate AD. Primary effi- cacy was measured by Investigator’s Global Assessment. After 4 weeks of treatment with the  ceramide-hyaluronic acid emollient foam, 82% of target lesions were scored clear or almost clear compared to 71% of target lesions under the pimecrolimus arm. The authors concluded that ceramide- hyaluronic acid emollient foam and pimecrolimus cream 1% work well in the treatment of AD in both children and adults with no associated adverse effects. Chamlin et al. assessed the efficacy of a newly developed, ceramide-dominant, physiologic lipid-based emollient, when substituted for currently used moisturizers, in 24 children who were also receiving standard therapy for stubborn-to-recalcitrant AD [53]. All subjects continued prior therapy (e.g., topical tacrolimus or corticosteroids), only substituting the barrier repair emollient for their prior moisturizer. Follow-up evaluations, which included SCORAD values and several biophysical measures of stratum corneum function, were performed every 3 weeks for 20 to 21 weeks. SCORAD values improved significantly in 22 of 24 patients by 3 weeks, with further progressive improvement in all patients between 6 and 20 or 21 weeks. TEWL, which was elevated over involved and uninvolved areas at entry, decreased in parallel with SCORAD scores and continued to decline even after SCORAD scores plateaued. Both stratum corneum integrity (cohesion) and hydration also improved slowly but significantly during therapy. Finally, the ultrastructure of the stratum corneum, treated with ceramide-dominant emollient, revealed extracellular lamellar membranes, which were largely absent in baseline stratum corneum samples. The authors concluded that a ceramide-dominant, barrier repair emollient represents a safe, useful adjunct to the treatment of childhood AD, and TEWL is at least as sensitive an indicator of fluctuations in AD disease activity as are SCORAD values. The study supports the outside-inside hypothesis as a component of pathogenesis in AD and other inflammatory dermatoses that are accompanied by a barrier abnormality.

EpiCeram consists of a specific combination of cera- mides, cholesterol, and fatty acids (in the ratio of 3:1:1) that mimics those naturally found in the skin [67, 68]. Recent studies have shown that EpiCeram has similar efficacy com- pared to a mid-potency topical corticosteroid but has a favor- able safety profile [67, 68]. However, these studies did not report objective measurements to demonstrate efficacy of treatment.

Increased TEWL and down-regulated antimicrobial pep- tides are observed in patients with AD. Park et al. investi- gated the relationship between antimicrobial and barrier fac- tors by measuring the changes of TEWL and antimicrobial peptides after topical application of tacrolimus and ceramide- dominant emollient in patients with AD [47]. A total of three patients with AD were treated with tacrolimus in one lesion and ceramide-dominant emollient in another lesion for 4 weeks. RT-PCR and western blotting revealed that the mRNA and protein expression levels of hBD-2 and LL-37 were increased on both study sites. Immunohistochemical analysis showed significant increase of antimicrobial pep- tides and interleukin-1a, while interleukin-4 was decreased on both study sites. The mean changes of TEWL and antimi- crobial peptides showed no statistical difference between both sites. The authors concluded that tacrolimus and cera- mide-dominant emollient influence on both TEWL and an- timicrobial peptides expression in patients with AD. It should be noted that in this study, the sample size was small and outcome measurements were focused.

Hon et al. evaluated whether the amount of emollient and skin cleanser used correlates with eczema severity, skin hy- dration or TEWL, and whether liberal usage alters disease severity, skin hydration, and TEWL [51]. The authors studied skin hydration and TEWL at three common TEWL measurement sites on the forearm (antecubital flexure, 20 mm below the antecubital flexure, mid-forearm) and determined the SCORAD score, Nottingham Eczema Sever- ity Score (NESS), Children’s Dermatology Life Quality In- dex (CDLQI) and the amount of emollient and cleanser  usage over a 2-week period in consecutive new patients seen at the paediatric skin clinic of a teaching hospital in Hong Kong. In total, 48 subjects and 19 controls were recruited. Patients with AD had significantly higher TEWL and lower skin hydration in the studied sites. Emollient and cleanser usage was significantly higher (p = 0.001 and p = 0.041, respectively) in patients with AD than in controls. The amount of emollient usage was correlated with NESS, SCORAD, CDLQI, TEWL and mid-forearm skin hydration. No such correlation was found with cleanser usage. Regardless of SCORAD, prescribing 130 g/m2/week of emollient met the requirement of 95.8% of patients, and 73 g/m2/week of emollient met that of 85.4%. As far as the cleanser is concerned, prescribing 136 g/m2/week met the requirement of 91.7% of patients. Although both skin dryness and skin hydration were improved, there was no significant improvement in SCORAD or TEWL after 2 weeks. In terms of global acceptability of treatment, three- quarters of patients with AD and controls rated the combination of cream and cleanser as 'good' or 'very good'. The authors concluded that adequate amounts of emollient and bathing cleanser should be prescribed to patients with AD. These amounts can be conveniently estimated based on body surface area instead of the less readily available tools for disease severity, degree of skin hydration or skin integrity. However, liberal usage of emollients and bathing cleanser alone does not seem to alter disease severity or TEWL within 2 weeks, implying that additional treatments are necessary to manage AD. Hence, liberal amounts of moisturizers should be used which can be conveniently esti- mated based on body surface area instead of the less readily available tools for disease severity, degree of skin hydration or skin integrity [51]. The outcome measures in this study included clinical scores, skin hydration, TEWL and global assessment of treatment measurements. In addition, the amount of emollient usage per unit body surface area per unit time was also assessed.

In another study, Hon et al. recruited 33 patients (mean age 12 years, SD 4 years) with AD to study the clinical and biophysiological effects of twice-daily application of a pseudo-ceramide containing cream [69]. Four weeks follow- ing the use of the pseudo-ceramide cream, the skin hydration significantly improved [mean (SD) from 30 [15] to 38 [15],  p = 0.039]. There was no deterioration in TEWL, eczema severity, or quality of life in these patients. The pseudo- ceramide cream improved the skin hydration but not the se- verity or quality of life over a 4-week usage. In this study, skin hydration and TEWL, disease severity (SCORAD in- dex), CDLQI, amount of topical corticosteroid usage, and a global assessment of treatment score were used as outcome measurements [69].

Among the various adverse effects of topical corticoster- oids, impairment of the epidermal permeability barrier is well-known. Decreased synthesis of the epidermal lipid con- sequently leads to structural defects of the stratum corneum. Recently, the beneficial effects of physiologic lipid mixtures containing pseudoceramide on the impaired epidermal per- meability barrier have been reported, which suggest that physiologic lipid mixtures may reduce the topical corticos- teroid-induced barrier impairment. The effect of a pseudoce- ramide-containing physiologic lipid mixture as a vehicle for a mid-potency topical corticosteroid was evaluated in an oxazolone-induced AD-like murine model [70]. The changes in TEWL, hydration and skin fold thickness were measured. Inflammatory cells in the dermis, including eosinophils, were counted and S. aureus binding assay was performed. Immunohistochemical staining for inflammatory cytokines and antimicrobial peptides were also performed. The topical corticosteroid in physiologic lipid mixture showed a signifi- cantly decreased infiltrate of inflammatory cells and a re- duced number of adherent S. aureus compared with the re- sults of the topical corticosteroid in polyethylene gly- col/ethanol vehicle. The authors concluded that the pseudo- ceramide-containing physiologic lipid mixture as a vehicle for a topical corticosteroid enhanced the anti-inflammatory effect of the topical corticosteroid and accelerated the skin barrier function restoration.

Kim et al. indirectly studied pseudoceramide-containing physiological lipid mixture by evaluating anti-inflammatory activity of topical hydrocortisone using a 12-O-tetra- decanoylphobol-13-acetate-induced skin edema model and topical corticosteroid induced adverse effects using hairless mice [71]. The investigators showed that the anti- inflammatory activity was not altered by co-application of either multi-lamellar emulsion (MLE) or hydrobase. MLE is a pseudoceramide-containing physiological lipid mixture which can restore and improve the barrier function of skin [72]. Co-application of MLE and 1.0% hydrocortisone showed less impairment in the epidermal permeability bar- rier function, skin hydration, and skin surface pH compared with hydrobase. Stratum corneum integrity, evaluated by measuring TEWL after repeated tape stripping, showed less damage with MLE co-application. Long-term application of topical hydrocortisone induced skin atrophy, measured by a reduction in skinfold and epidermal thickness and in the number of epidermal proliferating cell nucleus antigen (PCNA)-positive keratinocytes. Co-application of MLE did not affect the skinfold or epidermal thickness, but the num- ber of PCNA-positive keratinocytes was less decreased with MLE use. The investigators suggest that co-application of MLE is effective in reducing the local adverse effects of low-potency topical corticosteroids and supports the thera- peutic efficacy of physiological lipid mixtures on skin barrier function [71].

CURRENT & FUTURE DEVELOPMENTS

Research studies are being done to look at dermal deliv- ery systems which can best deliver an active substance through the stratum corneum and production of pseudocera- mides which possess properties necessary to improve water barrier function of the stratum corneum. Dermal delivery systems are compositions which typically contain skin per- meation enhancers which may induce structural transforma- tions of the bilamellar structure in the liquid crystalline in- terdomain regions, and thus promote transdermal delivery of pharmacological substances. Typical dermal delivery sys- tems have an alcohol or petroleum base, with little consid- eration given to the biological properties of the vehicle itself. The detergent properties can lead to disruption of the normal barrier function, which is counteractive to the potential bene- fit of the delivery system. Disruption of the normal barrier function often causes the stratum corneum to lose its natural barrier function potential. As a result, the skin becomes ei- ther too dry or too permeable to environmental substances. Other conventional delivery systems that are thought to pro- tect the skin from harmful substances are barrier ointments. The purpose of barrier ointments is to provide a film, and thereby create a layer which is impermeable to environ- mental substances. Due to the impermeability, these oint- ments increase the body temperature of the treated body part, as well as prevent perspiration, and thus render an uncom- fortable sensation. The aforementioned dermal delivery sys- tems are not formulated to deliver a substance to, or through, the human skin without permanently disrupting the stratum corneum's natural barrier function. Skold patented a dermal delivery system which contains skin permeation enhancers to deliver active ceramide-containing substances through the skin [73]. The delivery system comprises an aqueous carrier, wherein water comprises 65% or more of the delivery com- position by weight; a lipid component consisting of  fatty acid which comprises 0.5 to 10% by weight of the delivery composition, cholesterol which comprises 0.5 to 7% by weight of the delivery composition, and phospholipid and/or ceramide component which comprises 0.5 to 20% by weight of the delivery composition, wherein the phospholipid and/or ceramide component comprises 5% or more by weight phos- pholipid, and wherein the weight ratio of phospholipid/ceramide to cholesterol is 2:1 to 5.9:1; and optionally, skin lipid precursors, wherein a combination of said lipids comprises 2 to 20% by weight of the delivery composition

Critchley et al. disclosed a novel pseudoceramide which has the property similar to natural ceramides, but can be syn- thesized at a lower cost [74]. The pseudoceramide can be synthesized by ring opening the terminal epoxide ring of a glycidyl ether, using an amine, to provide a secondary amine. This secondary amine is then acylated with an ester or an acid chloride of a hydroxylated fatty acid or a nonhy- droxylated fatty acid with less than 10 carbon atoms, to ob- tain the required pseudoceramide.

Kobayashi et al. patented skin epidermal ceramide syn- thesis accelerators containing the N-acylated derivative or a salt of hydroxproline as an agent for improving skin barrier function for AD [75]. Park et al. disclosed a therapeutic agent for treating atopic dermatitis including the two cera- mide derivatives as active ingredients [76]. The same authors disclosed ceramide derivatives with straight or branched alkyl groups having 4 to 22 carbon atoms [77].

Snyergistic combination of a macrolide T-cell immuno- modulator or immunosuppressant [33-epichloro-33-desoxy- ascomycin) and a ceramide (ceramide 3, LPC-9S or linoleic acid) are provided in 2 patents, which are considered useful in the treatment of dermatological or mucosal diseases such as atopic or contact dermatitis or dry skin, asteatotic eczema or xerosis [77-79].

There are scanty published data to document the clinical efficacy of ceramide and pseudoceramide products and the delivery systems. More research studies are needed in this area.

CONCLUSION

Ceramides and pseudoceramide products aim to target on the pathophysiology of AD. A new concept in skin care is the incorporation of ceramides and pseudoceramide products into therapeutic moisturizers. Current research on efficacy of their use appears promising. Well designed, large scale, ran- domized, placebo-controlled trials to document therapeutic effects on disease severity, dermatologic biophysical pa- rameters, quality of life and patient acceptability are needed.

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