Skin pharmacology : the official journal of the Skin Pharmacology Society最新文献

Rabbit ears were single-pass perfused with a buffer solution containing either 6% hetastarch or 5% bovine serum albumin. Hydrocortisone 21-butyrate (5 mM), diflunisal (17 mM) or permethrin (33 mM) was added to isopropyl myristate with 5% polyethylene, and applied to about 40% of the epithelial surface area of the ear. Hydrocortisone 21-butyrate or permethrin were not found in the effluent with hetastarch or albumin. Following cutaneous ester hydrolysis, the appearance rate of hydrocortisone was about 4 pmol/min per cm2 in the hetastarch- or the albumin-containing buffer solution. No hydrolysis of permethrin was detected; the appearance rate of 3-phenoxybenzyl alcohol with 3-phenoxybenzoic acid corresponded to the absorption rate of the substrate impurities. During ex vivo perfusion of intact skin, serum albumin in the perfusion fluid may not enhance the appearance rate of xenobiotics in the effluent following dermal application when the distribution coefficient n-octanol/water is > 2,000 or when the xenobiotic is ionized at physiological pH. In general, for all substances investigated with our perfusion model thus far, the appearance rates decreased with rising distribution coefficient (n-octanol/buffer pH 7.4). High lipophilicity hinders the release from isopropyl myristate and the penetration through the skin.

The in vitro antifungal activity of tea oil, the essential oil of Melaleuca alternifolia, has been evaluated against 26 strains of various dermatophyte species, 54 yeasts, among them 32 strains of Candida albicans and other Candida sp. as well as 22 different Malassezia furfur strains. Minimum inhibitory concentrations (MIC) of tea tree oil were measured by agar dilution technique. Tea tree oil was found to be able to inhibit growth of all clinical fungal isolates. For the investigated dermatophytes MIC values from 1,112.5 to 4,450.0 micrograms/ml with a geometric mean of 1,431.5 micrograms/ml were demonstrated. Both C. albicans strains and the other strains belonging to the genus Candida and Trichosporon appeared to be slightly less susceptible to tea tree oil in vitro. However, their MIC values, which varied from 2,225.0 to 4,450.0 micrograms/ml (geometric mean 4,080 micrograms/ml), indicated moderate susceptibility to the essential oil of M. alternifolia. The lipophilic yeast M. furfur seemed to be most susceptible to tea tree oil. MIC values between 556.2 and 4,450.0 micrograms/ml (geometric mean 1,261.5 micrograms/ml) were found against the tested M. furfur strains. However, when calculated as percentage tea tree oil of the agar, the above-mentioned concentrations correspond to 0.5-0.44% tea tree oil content. These values are far below the usual relatively high therapeutic concentrations of the agent; approximately 5-10% solution or even the concentrated essential oil are used for external treatment. In comparison with tea tree oil, in vitro susceptibility against miconazole, an established topical antifungal, was tested. As expected, very low MIC values for miconazole were found for dermatophytes (geometric mean 0.2 microgram/ml), yeasts (geometric mean 1.0 microgram/ml), and M. furfur (geometric mean 2.34 micrograms/ml). It is suggested that the in vivo effect of tea tree oil ointment in the therapy of fungal infections of the skin and mucous membranes as well as in the treatment of dandruff, a mild form of seborrheic dermatitis, may be at least partly due to an antifungal activity of tea tree oil.

Corticosteroids and vitamin D3 analogues inhibit proliferation, enhance normal keratinisation and interfere with cutaneous inflammation in in vitro systems. Both treatments are effective in psoriasis, although several reports suggest that vitamin D3 is less effective in reducing the inflammatory changes compared to its potent effect on keratinocyte growth and differentiation. The aim of the present study was to compare and contrast the effects of the vitamin D3 analogue calcipotriol, clobetasol-17-propionate and a placebo on immunohistochemical markers for epidermal growth, keratinisation and inflammation induced by a standardised single challenge with ultraviolet B (UVB) radiation in normal human skin. Clobetasol proved to inhibit UVB-induced proliferation of epidermal cells, tenascin induction, keratin 16 induction and the accumulation of T lymphocytes and CD1a-positive cells. Epidermal thinning due to clobetasol was also observed. No effect of clobetasol was shown on the enhanced terminal differentiation following UVB challenge. In contrast, calcipotriol reduced the member of transglutaminase-positive cells following UVB challenge but increased the thickness of the epidermis without a significant effect on other markers for keratinisation, epidermal proliferation and inflammation. The present study reconfirms the potent effect of topical corticosteroids on various aspects of UVB-challenged skin. In contrast, calcipotriol interfered especially with one differentiation pathway (transglutaminase) without modulation of other UVB-induced changes.

Topical anesthesia of the skin, nowadays performed for various indications from pruritus over postherpetic neuralgia to minor surgery, has been under investigation for more than 30 years. Due to low water solubility, the active base form of most of the local anesthetics on the market is poorly absorbed through the skin. Hence, the most challenging target was to develop galenic preparations which provide a good skin penetration in order to reach the dermal nerve endings and thereby lead to sufficient local anesthesia. On the other hand good skin penetration also results in a distribution of the drug in the circulation. Since local anesthetic agents are known to have an impact on the heart and central nervous system, unwanted side effects following topical application onto the skin are worth discussing. This article reviews the current topical local anesthetics with particular accent on their pharmacological and toxicological data.

The accidental or therapeutic exposure of human skin to ionizing radiation is known to cause the radiation syndrome with its various manifestations. The aim of the study was to investigate the potential radioprotective effects of the protein-free hemodialysate Actovegin. After exposure to X-rays (single dose, 6 Gy), 70% of the cells died. In the presence of the hemodialysate, irradiation did not lead to cell death. Instead a slight increase in cell number was observed. A 5-fold increased cell number was found after 6 days when the cells were treated with the hemodialysate alone. To elucidate molecular mechanisms of the observed biological effects the correlation between the expression of the epidermal growth factor receptor (EGFR) and the demonstrated growth activation was investigated. Radiation alone resulted in a clear induction of EGFR, whereas the combination of irradiation and Actovegin treatment led to a strong downregulation after 2 days. Thus, the hemodialysate suppressed one of the radiation-induced effects. Further investigations have to elucidate the role of other proteins which are involved in the signal transduction cascade of tyrosine kinases (e.g. Ras, Raf, MAP kinases) leading to the transcription factor AP-1 in response to radiation under Actovegin treatment.

Previous studies have shown that acute disruption of the cutaneous permeability barrier by acetone results in an initial rapid phase of repair followed by a later, slower phase. In the present study, we demonstrate that manipulations which disrupt the barrier by other mechanisms, such as tape stripping or detergent treatment, have a similar pattern of barrier repair. In all three models, the return of lipid to the stratum corneum parallels the normalization of barrier function, and occlusion immediately after disrupting the barrier blocks both the return of lipid and the normalization of function. Moreover, occlusion beginning 6-8 h following barrier disruption blocks the late, slower phase of repair, indicating that the late phase can be inhibited independently of the initial phase. Lastly, both severe and relatively minor perturbations of the barrier elicit a repair response with a similar kinetic pattern. In summary, the present study demonstrates that barrier repair responses are similar regardless of the etiology or extent of barrier disruption.

Our previous studies revealed that topical minoxidil induced an increased rate of DNA synthesis in both dermal papilla and follicular germinal cells in early anagen and bulbar matrix as well as outer root sheath and perifollicular fibrocytic cells in mid and late anagen follicles in the bald scalp of the stump-tailed macaque. However, the epidermis and dermal fibrocytes showed no response. To determine the specific action of hypertrichotic agents on follicular cells, we examined the effects of two potent hypertrichotic agents, minoxidil and cyclosporin, on the DNA synthesis of cultured cells derived from either follicular cells (dermal papillar, perifollicular fibrocytic and outer root sheath cells) obtained from human and macaque scalps or nonfollicular cells (fibrocytes and epidermal keratinocytes) from human and macaque foreskin, palm and sole regions and the 3T3 cell line. Cultured subconfluent cells from the above follicular and nonfollicular specimens were incubated with either minoxidil (0.01-2 mM) or cyclosporin (0.01-100 mM) in medium (serum-free DMEM) for 48 h, then 3H-thymidine was added for the final 6 h. Minoxidil induced a significant increase in DNA synthesis in all follicular cells in a dose-specific manner (maximum rate at 0.5 mM for dermal papilla and perifollicular fibrocytic cells and 0.1 mM for outer root sheath cells). The perifollicular fibrocytic cells appeared to have a potentiality similar to that of the dermal papilla cells. Nonfollicular cells showed no response to minoxidil; 3T3 cells were rather suppressed. Cyclosporin appeared to have rather suppressive effects on both follicular and nonfollicular cells. These results suggest that minoxidil has a specific affinity to hair follicular cells and induced their cell proliferation. Although cyclosporin is known as a potent hypertrichotic agent, our studies on cultured follicular cells showed no direct proliferative effect. The hypertrichotic mechanism of cyclosporin appeared to be different from that of minoxidil.

Background: Retinaldehyde (RAL), a natural metabolite of beta-carotene and retinol (ROL), is tolerated by human skin after topical application.

Purpose: To see if topical application of a large quantity of RAL on human skin is associated with a detectable alteration of constitutive levels of plasma retinoids resulting from metabolism of RAL in the skin.

Methods: Plasma retinoids [ROL, all-trans-retinoic acid (all-trans-RA), RAL, retinyl palmitate/oleate, 13-cis-RA and 4-oxo-13-cis-RA] were analyzed by high-pressure liquid chromatography. Determinations were done in 10 healthy male volunteers kept on a vitamin-A-poor diet before, during and after daily topical application of 7 mg of RAL to 40% of the body surface for 14 days.

Results: The introduction of a restricted vitamin A diet before RAL application resulted in a decrease in the plasma levels of ROL, all-trans-RA and retinyl palmitate/oleate. Topical application of RAL did not induce an alteration of the plasma levels of retinoid metabolites. No RAL was detectable in any of the plasma samples.

Conclusion: The skin metabolism of topically applied RAL does not result in detectable alterations of constitutive levels of plasma retinoids in humans.

Using reverse transcriptase polymerase chain reaction we showed that freshly plucked human anagen hair expressed both type 1 (80 kD) and type 2 (60 kD) interleukin (IL)-1 receptor mRNAs. The IL-1 receptor type 1 was functional since after in vitro stimulation of plucked hair with IL-1 alpha, we observed the induction of mRNA(s) for the inflammatory cytokines IL-1 beta, tumour necrosis factor alpha and IL-6 as well as for the chemokines monocyte chemotactic and activating factor and IL-8. In addition, the growth of dissected human anagen hairs in culture in vitro was significantly and dose-dependently inhibited by IL-1 alpha as a consequence of hair bulb degradation. These observations, together with those of other authors in IL-1 alpha transgenic mice evidence the inhibitory role of IL-1 on human hair growth. Therefore, in order to identify individuals with high inflammatory potential in their hair follicle environment, we designed a rapid and simple assay to detect variations in the level of IL-1 alpha production in the overnight supernatant of plucked hairs in culture. We observed that 32.7% of the specimens from the volunteers tested (n = 116) could be considered highly inflammatory in terms of IL-1 alpha production. Altogether, these results suggest that in alopecia androgenetica, hair growth might be negatively influenced by IL-1, directly produced by the outer root sheath keratinocytes. Consequently, identifying the "inflammatory alopecic individual' might be of clinical interest to discriminate among individuals for whom anti-IL-1 strategies might be of therapeutic relevance.

The three retinoic acid receptors (RAR alpha, RAR beta and RAR gamma) are known to modulate the transcription of target genes through interaction of the individual receptors with their naturally occurring ligand, retinoic acid (RA). Since RA has multiple effects in vivo, considerable effort has recently been devoted to finding selective compounds to elucidate the functions of individual receptors and to relate these functions to specific in vivo effects. The racemic synthetic retinoid 6-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)hydroxy-methyl]-2- naphthalene carboxylic acid has recently been identified as an RAR gamma-selective agonist. A synthetic method involving lipase-mediated transformation has been developed to prepare the individual enantiomers. Discrimination between the two enantiomers is seen in both transcriptional activity and binding to recombinant receptors with the (S)-enantiomer being the more active. Differences between the two compounds are also seen in the Rhino mouse utriculi reduction assay and the rabbit irritation model. In both animal models, the (S)-enantiomer consistently gave a greater response. Taken together, these results suggest that the activity and irritation seen with RA and related compounds is receptor mediated. Further, the strong selectivity of the compounds reported here for RAR gamma suggests that this receptor plays an important role in these in vivo biological activities. The discrimination between these enantiomers may be useful in the design of novel retinoids with uniquely defined biological properties.