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

A non-invasive method for sampling skin surface lipids is cyanoacrylate stripping (CAC-TS). It was the purpose of our study to improve the method for sampling of skin surface lipids and the separation of epidermal lipid fractions by a modification of the methods described by Melnik and by Imokawa et al. Briefly, lipids on the glass slide sampled by CAC-TS from the forearm of 75 volunteers and from the forehead of 60 volunteers were eluted in hexane/ethanol under ultrasonication. Identification of the diluted total superficial sebaceous and epidermal skin lipids was performed by sequential high-performance thin-layer chromatography. For quantification of the lipids we used densitometric methods. By this modified method we were able to show a clear and complete separation of all relevant lipids from a cyanoacrylate strip that represented 1-2 mg stratum corneum only.

The micromorphological appearance of the psoriatic lesion is characterized by cutaneous inflammation, epidermal acanthosis and abnormal keratinization. The relevance of immunological factors has been reviewed in recent literature. Despite a longstanding interest of many centres in the pathogenesis of psoriasis, the position of epidermal proliferation, a key feature of the psoriatic plaque, remains to be established. The aim of the present review was to provide evidence from the literature and from our own work that enables us to answer the question to what extent epidermal proliferation might be a primary pathogenetic event or whether it represents a secondary phenomenon resulting from other abnormalities.

Mast cells are well known effector cells not only in allergic but also in diverse acute and chronic inflammatory diseases. We have shown previously that these cells produce a broad spectrum of cytokines which might contribute to mast cell-dependent pathology. In the present study, we have investigated the influence of four potent glucocorticoids, methylprednisolone-aceponate, methylprednisolone-17-propionate, prednicarbate, and betametasone valerate (10(-5) M-10(-9) M), on the IL-1 beta, IL-3, IL-8, and tumor necrosis factor alpha secretion of the HMC-1 mast cell line as measured by ELISA. All four glucocorticoids caused a comparable dose- and time-dependent inhibition of cytokine release from HMC-1 cells stimulated for 24 h with phorbol 12-myristate 13-acetate 25 ng/ml and calcium ionophore 2 x 10(-7) M. These results shed further light on the mechanisms involved in antiinflammatory effects of glucocorticoids in allergic inflammation.

The purpose of these studies was to compare directly the percutaneous absorption,excretion and metabolism of all-trans-retinoyl beta-glucuronide (RAG), a nontoxic retinoid, with all-trans-retinoic acid (RA) in the rat. Previously, it was demonstrated that topical treatment of human acne with either RAG or RA in cream resulted in a significant reduction of lesions. Whereas 0.1% RA showed adverse effects, concentrations of RAG up to 2.4% did not cause any adverse reactions. In the present studies, radiolabeled RAG or RA, dispersed in a water-based cream, was applied to the shaved dorsal skin of vitamin A-sufficient rats. Both RAG and RA were absorbed from the skin in a similar way. In both cases, radioactivity peaked in the plasma within 2-4 h and within the liver at 4-12 h. During a 7-day period, the overall excretion of radioactivity derived from RA and RAG in the feces and urine were similar, e.g. 17 and 12%, respectively. it is concluded that: (1) the transport, metabolism and excretion of topically applied radioactive RA and RAG are similar, although not identical, in the rat and (2) the toxic skin manifestations induced by RA but not by RAG cannot be attributed to major differences in their overall absorption, metabolism and excretion.

Opioid agents have been shown to protect against tissue damage caused by hypoxia/reperfusion, an event which has a significant reactive-oxygen-species (ROS) involvement. We have investigated the potential anti-inflammatory activity of three opioid agonists, DAMGO, DPDPE and U50488 in rat skin inflammation induced by the ROS hydrogen peroxide. The model involves the intradermal injection of the enzyme glucose oxidase which converts glucose to D-gluconic acid and H2O2 which is locally released. Following injection, a well-delineated inflammatory response develops rapidly, is maximal at 5 h and still measurable after 48 h. Co-administration of the delta or kappa opioid agonist DPDPE or U50488 (7.5-60 micrograms per site) significantly reduced the inflammation, in a dose-dependent manner, for periods of up to 3 h for DPDPE, and up to 5 h with U50488. The mu-opioid agonist DAMGO (7.5-60 micrograms per site) was ineffective. Co-administration of the opioid antagonist naltrexone (120 micrograms) partially reversed the anti-inflammatory effects of DPDPE and U50488. We conclude that the delta and kappa opioid receptor agonists DPDPE and U50488 are able to inhibit ROS-induced skin inflammation and that this may have clinical implications.

Clinical and in vitro evidence suggests that the physicochemical properties of the skin influence the process by which drugs are transported through skin. The effects of skin storage, preparation and pretreatment on the permeation and metabolism of (8-methoxypsoralen (8-MOP), as a model penetrant, were studied using the flow-through in vitro cell diffusion system. The metabolites and unchanged drug were estimated by thin-layer chromatography. While the permeability of 8-MOP was similar in fresh (445 cm.h-1) and azide-treated (449 cm.h-1) skin (p < 0.01), decreased permeability was observed in frozen skin (406 cm.h-1, p < 0.01). A 2.8-fold increase in the cumulative flux of 8-MOP at 24 h through azide-pretreated (2.5 x 10(-3) mumol.h-1.cm-1) versus fresh skin (9.1 x 10(-4) mumol.h-1.cm-1) was observed (p < 0.01). There was a slight increase in the flux of 8-MOP at 24 h when skin was frozen, compared with untreated skin. Increase in the flux of 8-MOP in frozen skin might result from the alteration of the molecular arrangement of the skin components during freezing. In addition to the obvious differences between frozen and fresh skin, these observations discourage the use of frozen skin. There is a moderate relationship between the permeability and flux of 8-MOP through frozen skin. A similar but nonrelated correlation was observed between the permeability and flux of 8-MOP through azide-treated skin samples (r = 0.6). These findings suggest that azide and freezing treatments lower the skin barrier properties to the transport of 8-MOP. Apparently, factors that may affect the inherent permeability of human skin, particularly those related to the handling, storage and pretreatment of skin with solvents and chemicals, can also influence topical drug delivery. The metabolic capacity of frozen skin and fresh skin remained constant during the period of study. These data may be of value in the development of topical methoxypsoralen systems. Further in vitro and in vivo studies are required to ascertain the generalization of this process.

Inhibitors of 5-lipoxygenase have been studied with respect to antipsoriatic efficacy. Of these compounds, R-68151 is of particular interest as it proved to inhibit 5-lipoxygenase without inhibiting 12-lipoxygenase, cyclooxygenase and thromboxane-A2 synthetase. R-68151 has been shown to have a mild-to-moderate therapeutic effect in psoriasis. In the present study a new 5-lipoxygenase, R-85355, was investigated with respect to its efficacy in psoriasis. R-85355 is 3 times more potent compared to R-68151 with respect to inhibition of in vitro A-23187-stimulated leukotriene-B4 production by polymorphonuclear leukocytes. In a left-right double-blind comparative study, the compound was studied at saturation with respect to its antipsoriatic efficacy in 11 patients with chronic stable plaque psoriasis. In addition, various markers for epidermal proliferation, keratinization and inflammation were assessed. In no single patient was a left-right difference observed in favour of R-85355 compared to placebo with respect to clinical severity scores or the cell-biological markers. The present study indicates that a selective and highly potent 5-lipoxygenase inhibitor was not effective in the topical treatment of chronic plaque psoriasis.

In order to define the respective involvement of steroidogenesis enzymes subtypes in the control of hair follicle homeostasis, we evaluated, by semiquantitative RT/PCR, the expression levels of mRNAs coding for 17 beta-hydroxysteroid dehydrogenase type 1 and type 2, 3 beta-hydroxysteroid dehydrogenase, Cyt.P450-aromatase, steroid 5 alpha-reductase type 1 and type 2 and 11 beta-hydroxysteroid dehydrogenase. These assays were performed for several components of the pilosebaceous unit (PSU); fresh plucked anagen hairs, sebaceous glands and primary culture of dermal papilla, as well as other tissues involved in an active steroid metabolism (human testis, liver, placenta, prostate, ovary, uterus and adrenals) as controls. We found that plucked hair (i.e. mainly keratinocytes from the inner and outer root sheaths) expressed: (1) very high levels of 17 beta-hydroxysteroid dehydrogenase type 2 corresponding to levels found in liver and placenta; (2) high levels of steroid 5-alpha-reductase type 1 corresponding to levels found in testis, liver and ovary, and moderate levels of 17 beta-hydroxysteroid dehydrogenase type 1, which corresponded to the expression in testis, prostate and uterus. In contrast, Cyt.P450-aromatase, 3 beta-hydroxysteroid dehydrogenase and steroid 5 alpha-reductase type 2 were poorly expressed in the pilosebaceous unit as compared with other tissues. Interestingly, expression patterns of these enzymes in primary cultures of dermal papilla were distinctive since 5 alpha-reductase type 1 and 11 beta-hydroxysteroid dehydrogenase were the only mRNA detected. Taken together, these results suggest that not only sebaceous gland but also outer root sheath keratinocytes may contribute, through the activity of the steroid 5 alpha-reductase type 1, to the pathogenesis of androgen-dependent alopecia.

The effects of mild inflammation induced by topical chloroform treatment on plasma extravasation and mast cell response were studied in normal innervated and denervated rat skin. In the absence of inflammation, the reduction in plasma protein extravasation in response to noxious heat was 31.2% in denervated skin compared to the innervated skin. In the presence of inflammation, the reduction in this response was 52.5% in denervated skin compared to the innervated skin. During inflammation, mast cells became abundant, highly degranulated and migrated to the lower dermal tissue forming large aggregations. The ultrastructural observations showed a close anatomical relationship between mast cells and vesicle-containing nerve profiles. These results indicate that repeated topical chloroform treatment of the rat skin induces neurogenic vascular inflammation accompanied by an increase in mast cell response.