Dealing with dandruff needs integrated approach
Dandruff, seborrhoeic dermatitis and psoriasis have in common that they are distinguished by excessive flaking. Differentiation between them sometimes is ill-defined. Species of Malassezia (and other germs) are considered to be involved as a cause or as a consequence in these skin conditions.
Especially in seborrhoeic dermatitis, oversecretion of oil glands (excessive formation of sebum) appears to be one responsible factor. However, seborrhoeic dermatitis sometimes is put on a level with severe oily dandruff. Otherwise, dandruff is sometimes also regarded as a light version of psoriasis. Apart from that, common features are enhanced renewal of the skin as well as inflamed skin that can be rather itchy. The conditions are complicated, interconnected and, therefore, in treatment a variety of pharmacological actions are conceivable to handle the different symptoms. As an example, dandruff (sometimes regarded as a cosmetic problem only) is described below in a more detailed way.
Dandruff is a phenomenon related to the renewal of the skin. In skin, regeneration cells formed at the inner side of the epidermis move to its outer side. On their way these keratinocytes are subjected to a transformation process at the end of which they mostly consist of lifeless keratin (corneocytes) that is cast off the skin in nearly invisible particles. However, this natural process can be impaired in such a way that it becomes a cosmetic problem with large agglomerates of corneocytes (scales) on scalp and hair. The origin of dandruff is still disputed. Often it is referred to as a vicious cycle in which, among other factors, genetic predisposition, the level of sebaceous activity and excessive colonisation with microorganisms are determinants. An enhanced proliferation rate in the epidermis causes an accelerated process of cell movement to the outer skin. In this case the adhesion between different cells cannot be resolved completely and scales appear. This process may appear with concomitant over-secretion of oil glands. The skin sebum and the oil soaked scales are like a nutrient substratum for microorganisms. Bacteria and fungi are found in the stratum corneum and in hair follicles. Staphylococcus epidermis, different Propionibacteria and Candida belong to the leading cutaneous microorganisms. (Malassezia spec. were given a major role by some researchers). Pathogens such as these increase in number and their lipolytic activity enhances the amount of free fatty acids on the scalp. These acids in their part may lead to irritations on the skin that are connected with itching and reddening. In principle, they are able to cause small inflammations on the skin. As a result a vicious circle may appear since inflammations can be the cause of an enhanced proliferation rate of epidermal cells.
Multifactorial picture and answer
As the clinical picture of dandruff, seborrhoeic dermatitis and psoriasis seems to involve or depend on a number of factors or causes (multifactorial), use of multifunctional active ingredients or utilisation of synergistic effects with combinations of active ingredients appears to be reasonable. For optimum results therefore, treatment schemes should take into account the whole multifactorial picture and should not rely on a monotherapy with an antifungal only (Bulmer and Bulmer, 1999). The performance of classically used antifungals (or in some cases antimicrobials) as, for example, ketoconazole, climbazole, piroctone olamine or zinc pyrithione often is enhanced by addition of salicylic acid. With its keratolytic action the last named helps remove scales (see e.g. Hickman, 2008). However, anti-inflammatory, sebosuppressive and anitproliferative actions are still missing in the treatment scheme.
Sodium shale oil sulfonate
One such active substance with a promising action profile is sodium shale oil sulfonate (SSOS) better known under its trade name Ichthyol Pale. SSOS is distinguished by an excellent tolerance which allows unrestricted application in cosmetics. Its use gives no hint of any toxic or phototoxic effect (Kandarova et al. 2005; Cholcha et al. 1994). As a multicomponent mixture of natural origin (see Figure 1 for an overview about its origin and manufacture), it features various pharmacological actions including antimicrobial effects. Investigations on the MIC and inhibiting zones developing in solid culture medium around chambers containing SSOS point towards substantial sensitivity of fungi to this substance (most sensible in the latter test: Malassezia spec.) (Grimm et al. 2001; Listemann et al. 1993; Leimbeck and Sonnenschein,1992). However, further actions important in treatment of flaking skin disorders (as described already) can be adduced. The anti-inflammatory action of sulfonated shale oils was investigated at the cellular level in vitro by some research groups. A special field of interest was the influence on pathways in the biosynthesis of eicosanoids and corresponding biological effects of different chemoattractants. As a result it could be revealed, among other aspects, that sulfonated shale oils inhibit the formation of inflammation mediators from eicosatetraenoic acids catalysed by lipoxygenases and cyclooxygenases in noncytotoxic concentrations of the test article. Furthermore, they are able to inhibit cell migration of leukocytes toward chemoattractants as LTB4 as well as other signal effects caused by them. This is regarded as one explanation for the efficacy of SSOS in treatment of inflammatory skin disorders (e.g. psoriasis) (see e.g. Schewe et al. 1994; Rabe et al. 1994; Czarnetzki, 1986). Apart from studies that deal with inflammation mediators, the antiinflammatory effect of SSOS could be revealed in vivo in human volunteers in the UVB erythema test as well. As a result of this test 4% pale sulfonated shale oil and 0.5% hydrocortisone had a significantly greater efficacy than the active ingredient free vehicle. What is more, there were no differences between the efficacy of 4% pale sulfonated shale oil and 0.5% of hydrocortisone in post-irradiation colour measurements (Warnecke and Wendt, 1998). The anti-seborrhoeic effect of orally administered sulfonated shale oils was demonstrated by Gloor in the early 1970s (Gloor et al. 1972). The antiseborrhoeic or sebosuppressive effect (squalene reduction) of locally applied pale sulfonated shale oil was revealed in a study dealing with the efficacy of a combination of chloramphenicol and pale sulfonated shale oil in the treatment of very severe acne (Fluhr et al. 1998). As it was pointed out, the combination of chloramphenicol and pale sulfonated shale oil appears reasonable as the antibacterial effect of chloramphenicol supplements the anti-comedogenic and sebosuppressive effects of pale sulfonated shale oil in the treatment of papulopustular acne. The evaluation of a lipid analysis after treatment of hair and scalp with a shampoo containing 2% of SSOS resulted in a significant reduction of the concentration of free cholesterol among the scalp lipids. Since free cholesterol originates from the perishing membranes in the stratum corneum it was assumed that its reduction is attributed to a thinning of the stratum corneum and to a reduction of the cell growth. These indirect findings point to an anti-proliferative effect of SSOS (Gloor et al. 1976). Such an effect was confirmed in another study in which the significant inhibition of mitoses compared with a surfactant vehicle was traced back to an anti-proliferative effect of SSOS (Gloor et al. 1978).
Combination treatment is recommended for patients who do not respond to a single agent (Sanfilippo and English, 2006). However, an optimum treatment should take into account the whole causality from the outset. The concept of combination shampoos bringing together different action principles is not new for SSOS. T/Gel Total by Johnson & Johnson (with the concept in its name) or Kertyol as well as Nodé by French consumer care giants Pierre Fabre and Bioderma are well known examples. However, it was only recently that SSOS was actually investigated in convincing controlled studies in comparison with coal tar, among other substances (Gayko et al. 2005). Two of the most recent studies with ketoconazole and calcipotriol (not published so far) as objects of comparison are described in more detail in the following text.
Combination with ketoconazole
Ketoconazole (KTZ) has become popular for dandruff shampoos in Europe since it can be used in cosmetic application up to a concentration of 2% (SCCNFP, 1999). In order to meet the requirements of an integrated approach anti-fungal ketoconazole was used at a reduced concentration (0.5%) together with SSOS (0.5%) (Gayko et al. 2006). The main goal of the randomised double-blind study was to find out if a combination of both agents actually offers a better prospect for success of treatment than a monotherapy with 1.0% of KTZ regarding symptoms scaling, redness and itching. Severity of dandruff (scaling, desquamation) was assessed by a four step score (0-3). Score 0, “no dandruff”, was defined as: “No scales are visible. No scales can be detached when scratching the scalp with a comb.” The opposite score 4, “severe dandruff”, was defined as: “Scales are clearly visible. Numerous scales can be detached from several places when scratching with a comb.” As secondary objectives, erythema and itching were examined. Skin redness was evaluated using a four step score system ranging from “0 = none” to “3 = severe”. Assessment of itching was a task for the subjects who were given a scale ranging from “0 = none” to “10 = severe”. Except for the content of KTZ and presence of SSOS, test shampoos had the same formula to guarantee comparability. In Figure 2 A - C the development of symptoms over a treatment time of four weeks is elucidated. Apparently, reduction of KTZ concentration did not have any influence on its anti-dandruff performance as scaling could be reduced by about 70% in both groups. However, there is a substantially faster effect with regard to improvement of itching with the combination of KTZ and SSOS (improvement of 71% after two weeks) than with KTZ alone (improvement of 56%). Starting with a low overall mean erythema score of 0.25 the KTZ 1% shampoo did not lead to any statistical significant results in erythema reduction in all treatment weeks. In week 4, a deterioration of the erythema score could be observed which is due to development of redness in three patients who were not affected before. In the KTZ/SSOS group 7 out of 11 patients were affected by skin redness on the day of the primary visit with a mean score of 0.73. No deterioration could be seen in patients treated with the combination shampoo. The improvement in skin redness by 75% after two weeks of treatment was followed by a total improvement of 88% in week 4. The excellent treatment results obtained for a combination of KTZ and SSOS unambiguously demonstrate that the concentration of active agent KTZ in a shampoo can be partly replaced by SSOS without loosing any efficacy. On the contrary, by addition of SSOS a better antidandruff performance with faster effects on the concomitant symptoms of dandruff (skin redness and itching) comes forward. In the KTZ group the intermediate deterioration in skin redness score in the course of treatment can be ascribed to the well-known side effects of this therapy. However, by addition of SSOS no such deterioration can be observed – rather, a quick response of the treatment on the erythema score is conspicuous. This observation is in accordance with the ability of SSOS to reduce skin redness as could be proved in the UVB erythema test. The combination shampoo is also better in reducing itching in a faster way as the improvement rates after two weeks of treatment clearly demonstrate. Whereas itching again is described as one of the side effects of topical KTZ therapy, SSOS is known for its efficient anti-itching effects which obviously contributed to the better outcome in this case. It might be concluded that synergistic effects can be obtained by combining KTZ and multifunctional SSOS in an anti-dandruff shampoo at a reduced concentration of the azole derivative. The latter is important as it means a higher safety margin for those who are concerned with the general toxicological profile of KTZ. Results obtained in this study are very much similar to those obtained in a prospective study in which patients suffering from seborrhoeic dermatitis of the scalp were treated with a shampoo for treatment of oily dandruff (KTZ 1%, SSOS and piroctone olamine as active ingredients) (Mirada et al. 2005). Although there was no control group, the most striking result was the quick improvement of symptoms. In two weeks erythema scores decreased from 1.76 to 0.20 (by 89%), desquamation from 2.24 to 0.44 (by 80%) and itching from 1.68 to 0.8 (by 52%). After 4 weeks all patients were virtually free from symptoms (final scores “0” for erythema and pruritus and “0.04” for desquamation). Tolerability of the shampoo was assessed to be “very well tolerated” in 92% of the cases (8% good). In light of the findings of the “KTZ/SSOS” study excellent results obtained in this case can be traced back to the presence of SSOS in the formulation as provider of a broad action profile actually addressing all the symptoms of the flaking skin disorder.
Comparison with calcipotriol
For proof of efficacy and tolerance of SSOS in psoriasis capitis a multicenter, prospective, randomised observer-blind study was conducted in 142 adult patients suffering from light to moderately severe psoriasis of the scalp (Mensing, 2008). General suitability of SSOS for treatment of psoriasis capitis could be already confirmed in a non-interventional study by treatment of 24 out of altogether 49 subjects suffering from psoriasis of the scalp (Fischer and Mays, 1996) (Psoriasis, part of a non-interventional study in a post-market survey of Ichthoderm Cream titled: Ichthoderm® in seborrhoeic dermatitis of the scalp and psoriasis of the scalp). Goal of the present study was the proof of non-inferiority of 2.0% of SSOS in a rinsable cream base in comparison with 0.005% of calcipotriol (calcipotriene) in a solution based on 2-propanol. Calcipotriol is a synthetic derivative of calcipriol or vitamin D. Vitamin D3 analoga are used in a standard therapy in moderately severe skin plagues which appear to control skin cell growth and improve differentiation of keratinocytes. Futhermore, they act antiinflammatorily by different mechanisms (for an overview see e.g. Fuhrmeister, 2001, and the literature referred to therein). Maximum treatment time in this study was 4 weeks. After initial examination progress of treatment was investigated after 1, 2 and 4 weeks. Main objective under assessment was the change of total score including desquamation, infiltration, erythema, itching and extension of the affected skin areas after 4 weeks of treatment in comparison with the initial examination. However, an isolated assessment of the aforementioned symptoms as well as the extension of affected skin areas was made as well. For assessment the investigators used a five step score between “0 = no symptom” and “4 = very severe condition”. Application of the SSOS cream (Ichthoderm) was carried out every 2 days overnight. The cream was rinsed off in the morning with an active ingredient free mild shampoo. The solution of calcipotriol was administered two times daily on the affected scalp. Patients in this group were instructed to wash their hair every two days with the same active ingredient free shampoo. Application of any further medication (systemically or topically) was not allowed. As a result of this study the total score could be reduced by 50% in both groups. Thereby, non-inferiority of SSOS in comparison with calicipotriol could be confirmed statistically. The equivalence of both therapies is reflected by the results in the secondary objectives as well. As an example, in Figure 3 A – C the improvement in secondary objectives desquamation, skin redness and itching is elucidated. In summary, the results of this clinical study give evidence of an equivalent good efficacy (non-inferiority) of a cream containing 2% of SSOS and a frequently prescribed medicinal product containing calcipotriol in a 2-propanol solution in treatment of psoriasis of the scalp. This is true for the main objective as well as all secondary objectives. At the same time, the SSOS cream is clearly superior to calcipotriol with regard to tolerance. The investigators assessed the tolerance of the SSOS cream as very good in 49.3% of all cases whereas the same assessment was made for the calcipotriol group only in 31.3%. Psoriasis is a potentially chronically recurring skin disorder. For its treatment the tolerance of applied medicinal products is of great importance as a large part of affected persons have to be treated frequently over long periods. The safety of sulfonated shale oils is specially noteworthy as therapeutical alternatives registered for this indication often lead to undesirable side effects.
Sodium shale oil sulfonate suggests itself for treatment of scaling skin disorders such as dandruff and psoriasis of the scalp on account of its multifunctionality together with natural origin and good tolerance. It offers the basis for a functionally combined therapy with one active ingredient only as the comparison study with potent vitamin D3 analog calcipotriol unambiguously demonstrates. Symptoms occurring together with dandruff or as a result of its aggressive treatment (skin redness, inflammation and agonising itching) are countered effectively. At the same time, sodium shale oil sulfonate can be used to add additional actions to the standard therapy of scaling skin disorders by means of antifungal agents (see table). Synergistic effects might be expected in combination shampoos at a reduced concentration of antifungal agents e.g. azole derivatives. This is also important with respect to side effects often experienced with the latter. Thereby, an integrated approach is not only helpful to treat all symptoms at the same time but also to help improve the overall tolerance.
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