Showing papers in "Skin Pharmacology and Physiology in 2006"

The pH of the skin surface and its impact on the barrier function.

Abstract: The ‘acid mantle’ of the stratum corneum seems to be important for both permeability barrier formation and cutaneous antimicrobial defense. However, the origin of the acidic pH, measurable on the skin

Overcoming the stratum corneum: the modulation of skin penetration. A review.

Abstract: It is preferred that topically administered drugs act either dermally or transdermally. For that reason they have to penetrate into the deeper skin layers or permeate the skin. The outermost layer of the human skin, the stratum corneum, is responsible for its barrier function. Most topically administered drugs do not have the ability to penetrate the stratum corneum. In these cases modulations of the skin penetration profiles of these drugs and skin barrier manipulations are necessary. A skin penetration enhancement can be achieved either chemically, physically or by use of appropriate formulations. Numerous chemical compounds have been evaluated for penetration-enhancing activity, and different modes of action have been identified for skin penetration enhancement. In addition to chemical methods, skin penetration of drugs can be improved by physical options such as iontophoresis and phonophoresis, as well as by combinations of both chemical and physical methods or by combinations of several physical methods. There are cases where skin penetration of the drug used in the formulation is not the aim of the topical administration. Penetration reducers can be used to prevent chemicals entering the systemic circulation. This article concentrates on the progress made mainly over the last decade by use of chemical penetration enhancers. The different action modes of these substances are explained, including the basic principles of the physical skin penetration enhancement techniques and examples for their application.

Hair follicles - a long-term reservoir for drug delivery.

Abstract: Nanoparticles represent an important drug carrier system. Recently, we have reported on the penetration and storage behavior of particular and non-particular substances revealing the superiority of pa

Influence of nanoencapsulation on human skin transport of flufenamic acid.

Abstract: The effect of the inclusion of flufenamic acid in poly(lactide-co-glycolide) nanoparticles on the transport of flufenamic acid into excised human skin was investigated. Penetration and permeation data were acquired using two different in vitro test systems: the Saarbrucken penetration model, where the skin acts as its own receptor medium, and the Franz diffusion cell, where the receptor medium is a buffer solution. For the stratum corneum, no differences were found between nanoencapsulated and free drug. Drug accumulation in the deeper skin layers and drug transport across human epidermis were slightly delayed for the nanoencapsulated drug compared to the free drug after shorter incubation times ( 12 h), the nanoencapsulated drug showed a statistically significantly enhanced transport and accumulation (p < 0.05). Additionally, nanoencapsulated flufenamic acid was visualized by multiphoton fluorescence microscopy. Particles were found homogeneously distributed on the skin surface and within the dermatoglyphs, but no nanoparticles were detected within or between the corneocytes.

In vivo drug screening in human skin using femtosecond laser multiphoton tomography.

Abstract: The novel femtosecond laser multiphoton imaging system DermaInspect forin vivotomography of human skin was used to study the diffusion and intradermal accumulation of topically applied cosmetic and ph

Novel Drug Delivery Systems: Potential in Improving Topical Delivery of Antiacne Agents

Abstract: Acne is the most common cutaneous disorder of multifactorial origin with a prevalence of 70–85% in adolescents. The majority of the acne sufferers exhibit mild to moderate acne initially, which progre

Tight junction proteins in the skin.

Abstract: It has long been accepted that tight junctions (TJ) are crucial for the formation and maintenance of the paracellular barrier and for cell polarity in simple epithelia and endothelia. Moreover, it is long known that they play a role in barrier function of amphibian skin. However, only in recent years were TJ and TJ proteins identified in the epidermis of men and mice. Their involvement in the barrier function of mammalian skin has been shown. This review summarizes our current knowledge about TJ and TJ proteins in mammalian skin.

Antioxidant supplements improve parameters related to skin structure in humans.

Abstract: In the present study we investigated the influence of two different antioxidant supplements composed of carotenoids, vitamin E and selenium on parameters related to skin health and skin aging. Thirty-nine volunteers with healthy, normal skin of skin type 2 were divided into 3 groups (n = 13) and supplemented for a period of 12 weeks. Group 1 received a mixture of lycopene (3 mg/day), lutein (3 mg/day), beta-carotene (4.8 mg/day), alpha-tocopherol (10 mg/day) and selenium (75 microg/day). Group 2 was supplemented with a mixture of lycopene (6 mg/day), beta-carotene (4.8 mg/day), alpha-tocopherol (10 mg/day) and selenium (75 microg/day). Group 3 was the placebo control. Upon supplementation serum levels of selected carotenoids increased in both verum groups. Skin density and thickness were determined by ultrasound measurements. A significant increase for both parameters was determined in the verum groups. Roughness, scaling, smoothness and wrinkling of the skin were determined by Surface Evaluation of Living Skin (Visioscan). Roughness and scaling were improved by the supplementation with antioxidant micronutrients. In the placebo group no changes were found for any of the parameters.

In vitro 5-lipoxygenase and anti-oxidant activities of South African medicinal plants commonly used topically for skin diseases.

Abstract: An investigation was undertaken to determine the possible mechanisms of action of medicinal plants used for dermatological pathologies. A total of 14 plant species were selected from the readily avail

Effect of Supplemented and Topically Applied Antioxidant Substances on Human Tissue

Abstract: Systemic and topical application of antioxidant substances for the medical treatment and prophylaxis of many diseases as well as additional protection of the skin against the destructive action of free radicals and other reactive species has become very popular during the past years. Stimulated by the positive results of a fruit and vegetable diet in supporting medical treatment and in cosmetics, artificial and extracted antioxidant substances have been broadly applied. Surprisingly, not only positive but also strong negative results have been obtained by different authors. According to study reports artificial and extracted antioxidant substances support different kinds of medical therapies, if they are applied in mixtures of different compounds at low concentration levels. In the case of the application of high concentration of some single compounds, side effects were often observed. Regarding skin treatment by systemically applied antioxidant substances for cosmetic purposes, positive cosmetic effects as well as no effects, but almost no side effects, apart from a number of allergic reactions, were reported. One reason for this seems to be the lower concentration of systemically applied antioxidant substances in comparison with a medical application. Topical application of antioxidant substances is closely related to cosmetic treatment for skin protection and anti-aging. Positive results were also obtained in this case. The present review is an attempt to classify and summarize the published literature concerning the efficiency of action of systemic and topical applications of antioxidant substances, such as carotenoids and vitamins, on human organism and especially on the skin. The available literature on this topic is very extensive and the results are often contradictory. Nevertheless, there are some clear tendencies concerning systemic and topical application of antioxidant substances in medicine and cosmetics, and we summarize them in the present paper.

Follicular Penetration: Development of a Method to Block the Follicles Selectively against the Penetration of Topically Applied Substances

Abstract: Investigations into the penetration pathways of topically applied substances through the skin play an important role in dermatological science. Recently, the hair follicles have increasingly been recognized as an important pathway for percutaneous penetration, although the role of the follicles has still not been clarified in detail. Therefore, the aim of the present study was to develop an in vivo method for the analysis of the follicular rate of penetration processes. In order to reach this goal, the follicles were excluded from the penetration process of topically applied substances. Different study designs were evaluated, and we were able to show that the application of nail varnish to each follicular orifice represents an effective method of blocking the follicles selectively against the penetration of topically applied substances. In dermatological science, there is new information on the physiology of skin penetration processes, thus allowing examination of the follicular rate of penetration and improvement of the pharmacokinetics of topically applied substances.

An in vivo Randomized Study of Human Skin Moisturization by a New Confocal Raman Fiber-Optic Microprobe: Assessment of a Glycerol-Based Hydration Cream

Abstract: Background: In a recent study, we demonstrated the ability of the new confocal Raman microprobe to investigate molecular and structural human skin composition under in vivo conditio

Treatment of Head and Neck Dermatitis with Ciclopiroxolamine Cream – Results of a Double-Blind, Placebo-Controlled Study

Abstract: In atopic dermatitis, microbial allergens may be pathogenetically significant. Apart from Staphyloccocus aureus, these are primarily lipophilic Malassezia yeasts.

Sodium lauryl sulfate-induced irritation in the human face: regional and age-related differences.

Abstract: The particular sensitivity of the human face to care products prompted us to study irritation induced by sodium lauryl sulfate (SLS) in its various regions. We examined regional and age-related differ

'Keratolytic' properties of benzoyl peroxide and retinoic acid resemble salicylic acid in man.

Abstract: Objectives: Retinoic acid (RA) and benzoyl peroxide (BP) were studied, comparing their keratolytic efficacy and water barrier disruption to that of salicylic acid (SA), a well-estab

Effect of 5α-Dihydrotestosterone and Testosterone on Apoptosis in Human Dermal Papilla Cells

Abstract: Pathogenetic mechanisms in androgenetic alopecia are not yet fully understood; however, it is commonly accepted that androgens like testosterone (T) and 5alpha-dihydrotestosterone (5alpha-DHT) inhibit hair follicle activity with early induction of the catagen. Thus, we investigated the influence of T and 5alpha-DHT on proliferation, cell death and bcl-2/bax expression in cultured dermal papilla cells (DPC) from nonbalding scalp regions of healthy volunteers. T and 5alpha-DHT induced apoptosis in DPC in a dose-dependent and time-related manner; in addition a necrotic effect due to T at 10(-5) M was found. Interestingly, bcl-2 protein expression was decreased in T- and 5alpha-DHT-treated cells, leading to an increase in the bax/bcl-2 ratio. In addition, T and 5alpha-DHT induced proteolytic cleavage of caspase 8 and inhibited proliferation of DPC at 10(-5) M. High concentrations of T and 5alpha-DHT were needed to induce apoptotic effects in DPC. These data suggest that DPC from nonbalding scalp regions do have the capacity to undergo apoptosis, but need a high androgen stimulus. The present study provides an interesting new pathogenetic approach in androgenetic alopecia.

Are sweat glands an alternate penetration pathway? Understanding the morphological complexity of the axillary sweat gland apparatus.

Abstract: To build an effective barrier against the penetration of extrinsic agents is one of the skin's main functions. The barrier properties of the stratum corneum and the epidermis have been subject to extensive studies in the past while the role of skin appendages as possible pathways of penetration are only rarely described. In order to study the possible penetration barriers in these complex appendages, a careful investigation of their morphology and ultrastructure has to be done. Studying the morphology of axillary skin appendages requires clear-cut criteria for the differentiation between eccrine, apocrine and apoeccrine glands. Therefore we studied the distribution of proteins described to be specific for either eccrine or apocrine glands (CD15, CD44, S-100 and milk fat globulin) on axillary skin samples from healthy young adults by immunofluorescence. Additionally, we examined the distribution of cytoskeletal proteins such as cytokeratins (1/10/11, 14, 18) and F-actin. For a more detailed understanding of the possible versatile barrier elements of the axillary sweat glands, we studied the distribution of tight-junction-associated proteins (occludin, claudin 1, claudin 4). The coils and the dermal duct may provide an active barrier built of tight junctions as occludin and claudin 4 are co-localized. However, the intra-epidermal duct did not show any co-localization of the investigated proteins. By combining morphological features as revealed by F-actin staining and the distribution of the above-mentioned proteins, immunocytochemical typing of eccrine and apocrine glands becomes possible. With this tool, we could also confirm the existence of apoeccrine glands and locate them in their 'natural environment'.

Percutaneous absorption of steroids: determination of in vitro permeability and tissue reservoir characteristics in human skin layers.

Abstract: The skin localization of steroids following topical application is largely unknown. We determined the distribution of five steroids in human skin using excised epidermal, dermal, and full-thickness me

Skin Ultrastructure in Senile Lentigo

Abstract: Senile lentigo is a common component of photoaged skin. It is characterized by hyperpigmented macules which affect chronically irradiated skin mostly after the age of 50. This study was undertaken to assess the morphology of senile lentigo on the dorsum of the hands. A systematic comparison between lesional and perilesional skin using histology and transmission electron microscopy was done to determine whether melanocytes or keratinocytes are affected in the evolution of lesions and which tissue structure is modified. The histology study showed that lesional skin is characterized by a hyperpigmented basal layer and an elongation of the rete ridges, which seem to drive deeply into the dermis. The epidermis contained clusters of keratinocytes, which retained and accumulated the melanin pigment. Electron microscopy studies showed important modifications in the lesional skin ultrastructure in comparison with perilesional skin. In melanocytes from perilesional and lesional skin, we observed normal size melanosomes at all stages of maturation in the cytoplasm and in migration within dendrites. No pigment accumulation was observed. However, the morphology of melanocytes in lesional skin revealed an activated status with numerous mitochondria and a well-developed endoplasmic reticulum, which could reflect intense protein synthesis. In basal keratinocytes from lesional skin, we observed numerous melanosome complexes called polymelanosomes, which formed massive caps on the nuclei. Observations in colored semi-thin sections also revealed perturbed structures in the basal layer region, which could explain the skin perturbation. Indeed, we observed keratinocytes that presented important microinvaginations and pendulum melanocytes, which sank into the dermis, beneath the basal layer of keratinocytes. These cell modifications seemed to be due to a perturbation of the dermal-epidermal junction, which appeared disorganized and disrupted and could directly disturb the basal support of the cells.

Reduced cellular toxicity of a new silver-containing antimicrobial dressing and clinical performance in non-healing wounds.

Abstract: Bacterial colonisation of wounds may delay wound healing. Modern silver-containing dressings are antimicrobial, yet cellular toxicity is a serious side-effect. We provide data for a newly formulated s

Ethnic Variation in Vellus Hair Follicle Size and Distribution

Abstract: It is a given fact that hair follicles play an important role in the penetration process of topically applied drugs and cosmetics. Since exact knowledge of the potential follicular reservoir is essential for understanding and calculating the penetration process, this knowledge may indeed help to optimize the development of topically applied drugs and cosmetic products. We know that variability in skin properties exists among the human population, but it is the deciphering and quantification of these differences that may help to explain racial disparities in dermatological disorders and provide a basic approach for treatment and prevention. Data pertaining to structural and functional differences within ethnic skin types (reviewed in this paper) support the assumption that hair follicles in the various skin types are not equal. Thus, the need to investigate follicular morphology in non-Caucasian skin types becomes more than apparent. The aim of the present study was to determine the potential reservoir of vellus hair follicles in non-Caucasian skin types in order to estimate their contribution to the penetration of topically applied substances. Cyanoacrylate skin surface biopsies were taken from seven body sites of Asians and African-Americans. To determine the follicular reservoir, the samples were evaluated under the light microscope. Follicular parameters were measured with the help of a digital imaging software program. In the evaluation and comparison of the results with those of Caucasians, significant differences were detected. Compared with Whites, follicular density on the forehead is significantly lower in Asians and African-Americans. Smaller values were detected for volume, surface, follicular orifice and hair shaft diameter on the thigh and in calf regions in Asians and African-Americans. Furthermore, the follicular reservoir, characterized by follicular volume, is generally higher in Caucasians. In comparison to African-Americans, larger follicular volumes on the forehead, back and on the upper arm were determined in Asians. The fairly similar density in these sites revealed that Asians have a higher follicular reservoir in these sites. Due to significant ethnic differences in the follicular reservoir, particularly on the calf and forehead, prospective skin absorption experiments need to be performed on different skin types in order to be representative. Likewise, the development of topically applied drugs should take place under adequate consideration of ethnic differences in skin physiology.

The Role of Menthol in Skin Penetration from Topical Formulations of Ibuprofen 5% in vivo

Abstract: In vivo plasma profiles from formulations containing 5% ibuprofen were compared after a single topical application in a randomised, double-blind, cross-over trial. IbuleveTM gel (Dermal Laboratories, UK) contained only ibuprofen whilst Deep ReliefTM gel (Mentholatum, UK) also contained 3% menthol. In contrast to results obtained when these products were compared under in vitro conditions, there was no statistically significant difference in vivo between delivery of ibuprofen. Estimated relative bioavailability fraction (Deep Relief gel/Ibuleve gel) from log-transformed AUC(0–24h) was 0.99 (95% CI: 0.94–1.04), estimated Cmax ratio was 0.96 (95% CI: 0.91–1.00) and estimated tmax ratio was 1.01 (95% CI: 0.81–1.20). Menthol produces local vasodilation, which reduces skin barrier function, and these data demonstrate that it is inappropriate to extrapolate from in vitro data where formulation components produce biologically-mediated enhancement of permeation which cannot be modelled ex vivo. In clinical use, these products deliver comparable amounts of ibuprofen, but only Deep Reliefgel provides the secondary immediate benefit of the direct analgesic action of menthol.

Thermal behaviour of human stratum corneum. A differential scanning calorimetry study at high scanning rates.

Abstract: Purpose: To use high-speed differential scanning calorimetry (DSC) in the identification of transitions in human stratum corneum (SC). Several scanning rates (100°C/min to 400°C/min) are used. Results: Eight transitions from 0 to 120°C are detected in a significant number of samples. Most of these transitions have already been identified in previous studies, but have been labeled considering essentially that only four are present. Results also indicate some degree of reversibility for transitions occurring at temperatures above 90°C. Dehydrated SC samples displayed slightly more defined transition peaks and a less frequent presence of the transitions below 50°C. In turn, the delipidised SC matrix showed two major endothermic signals, centered around 55 and 100°C, in conjunction with other much less marked features. Conclusions: The interpretation of DSC traces in terms of four main transition temperatures must be complemented having in mind the occurrence of other transitions, some of them at physiological temperatures. This work further suggests that transitions at temperatures above 90°C may to a large degree be associated to lipids, while transition at approx. 55°C is probably related to lipids covalently linked to proteins, as previously suggested.

Increased soluble E-cadherin in melanoma patients.

Abstract: Cadherin switching is thought to contribute to melanoma progression. E-cadherin expression is downregulated, facilitating the release of contacts with keratinocytes, while N-cadherin expression is increased, potentially contributing to more migration. Proteolytic cleavage of the cadherin extracellular domain, a process called ectodomain shedding, is one way to decrease cadherin cell surface expression. In addition, the released ectodomain could actively contribute to a more invasive phenotype. To examine if melanoma progression correlates with increased cadherin ectodomain shedding, we tested the presence of N- and E-cadherin extracellular domains in different melanoma cell lines and the presence of E-cadherin in sera of patients. Shedding occurs and is regulated in several melanoma cell lines expressing these cadherins. No correlation could be found between cadherin shedding and invasive capacity of the cell lines. However, we did find a significant increase in serum E-cadherin levels of melanoma patients with advanced disease correlating with increased S100 tumor marker values, suggesting that increased cadherin shedding may contribute to melanoma progression.

Semiquantitative determination of the penetration of a fluorescent hydrogel formulation into the hair follicle with and without follicular closure by microparticles by means of differential stripping.

Abstract: Recently, hair follicles were shown to be of great importance concerning the penetration and reservoir behavior of topically applied substances. Especially microparticles are known to be efficient dru

Activity of the triazole antifungal r126638 as assessed by corneofungimetry.

Abstract: Background: R126638 is a novel triazole exhibiting potent in vitro and in vivo antifungal activity against fungal pathogens including dermatophytes and yeasts. Objective: To determine the antifungal activity in time in the stratum corneum of healthy volunteers after oral intake of R126638 at a daily dose of 100 or 200 mg for 1 week. Method: Sixteen male volunteers were randomly allocated to oral treatment with either 100 or 200 mg of R126638 once daily for 1 week. Five cyanoacrylate skin surface strippings (CSSS) were obtained from the forearm of each subject before drug intake at day 1. CSSS were also collected during treatment at day 2 (24 h after the first drug intake, before the second drug intake), at day 4 (before the fourth drug intake) and at day 7 (10 h after the last drug intake). The post-treatment lingering effect was assessed at day 10 (3 days after treatment) and at day 14 (7 days after treatment). The corneofungimetry bioassay was performed on these CSSS to assess the antifungal profile of R126638. Cells of different fungal species (Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, Candida albicans and Malassezia globosa) were deposited and cultured for 10 days on CSSS in a sterile and controlled environment. The extent of fungal growth on the stratum corneum was determined using computerized image analysis. Results: R126638 clearly reduced the growth of all tested fungal species. The onset of effects of R126638 was evidenced at day 4 when it reached statistical significance for 3 of 5 species. At day 7, significance was reached for 4 of 5 species. During the posttreatment period, R126638 remained effective for 4 of 5 species at day 10, and this activity persisted until day 14 for 2 of 5 species. Conclusion: A broad spectrum antifungal activity was rapidly expressed in the stratum corneum after oral intake of R126638. The drug likely reached the upper layers of the stratum corneum by diffusion and persisted in this location for at least 7 days after treatment.

Chronobiology: biological clocks and rhythms of the skin

Abstract: The cyclicity of time affects virtually all aspects of our being and is the basis of the underlying rhythmicity which is typical of our lives. To ‘tell time’, most living organisms use internal timing

Accelerated healing of excisional skin wounds by PL 14736 in alloxan-hyperglycemic rats.

Abstract: PL 14736 is a synthetic peptide, originally isolated from human gastric juice, that has anti-inflammatory and tissue-protective actions in experimental models of gastrointestinal inflammation. To inve

Natural scalp hair regression in preclinical stages of male androgenetic alopecia and its reversal by finasteride.

Abstract: Using contrast-enhanced phototrichogram (CE-PTG) at monthly intervals during 48 months, we measured the duration of the hair cycle, i.e. anagen, catagen and telogen at the exclusion of exogen. Exogen, a recently identified phase of the hair cycle, is characterized by weakening of anchorage of the club hair to the surrounding epithelium. The processing of the club hair terminates at the time of exogen hair release, i.e. hair shedding. We combined a noninvasive exogen sampling before each CE-PTG so that the area contained only anagen, catagen and telogen hair or empty follicular openings. During the first 24 months of this study, natural regression of hair cycling in early i.e. preclinical stages of androgenetic alopecia (AGA) in androgen sensitive areas was documented. Shortening of the hair cycle of thicker hair characterized progression of AGA. During the next 24 months, finasteride (1 mg/day) was introduced into the system. Shortening of the hair cycle was reversed by finasteride in androgen sensitive sites as long as the affected follicle was able to produce a thick hair fiber at the time of treatment initiation. Compared to the baseline period, responding follicles did not produce thicker hair. On average, they initiated active growth more rapidly by reducing the duration of the lag phase by 40%. The duration of the anagen phase of thick hair showed an average 23% increase. In this particular experiment, the already miniaturized follicles producing thinner hair (

Current state and perspectives of dendritic cell vaccination in cancer immunotherapy.

Abstract: Recent progress in the approach towards immunotherapy of cancer consists in molecular definition of tumor antigens, new tools for phenotypical and functional characterization of tumor-specific effector cells and clinical use of novel adjuvants for optimal stimulation of a cancer-specific immune response such as dendritic cells. In spite of these advances and immunological as well as clinical responses in selected patients, mechanisms involved in dendritic-cell-based cancer immunotherapy are still poorly understood. Therefore, a standardized study design and small pilot trials are needed to explore open scientific questions in future clinical trials. This review focuses on the different parameters of dendritic cell biology relevant to cancer immunotherapy and on innovative approaches to hopefully enhance the efficacy of dendritic cell vaccination.