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PubMed1990

Shed snake skin and hairless mouse skin as model membranes for human skin during permeation studies.

Difficulties in obtaining and using human skin have tempted many workers to employ animal membranes for percutaneous absorption studies. We have investigated the suitability of two species of snake (Elaphe obsoleta, Python molurus) for this purpose and compared our in vitro experimental results for human skin and for hairless mouse, a currently popular model. The effects of long-term hydration on the membranes were investigated over 8 d using tritiated water as a model permeant. The initial permeability coefficients of all the membranes were similar (0.74-2.2 X 10(-3) cm 2h-1). Although the human and squamate skins did not change significantly over the test period, the permeability of hairless mouse skin increased 37 times. The actions of typical enhancers on the permeabilities of the membranes to a model penetrant 5-fluorouracil (5-FU) were tested using 3% Azone in Tween 20/saline, propylene glycol (PG), 2% Azone in PG, and 5% oleic acid in PG. While the data from snake membranes tended to underestimate the enhancer effects, those from hairless mouse skin greatly overestimated the changes. None of the membranes was a completely reliable model for assessing human percutaneous absorption as modified by accelerants. Pretreatment with acetone did not significantly change the permeability of human or squamate skins to 5-FU, although that of hairless mouse increased twentyfold. An overall conclusion is that, wherever possible, human skin should be used in absorption studies and not hairless mouse or snake skin; otherwise, misleading results may be obtained.

Acetone↗
PubMedDate not supplied

The 1999 clinical research award. Cultured skin substitutes combined with Integra Artificial Skin to replace native skin autograft and allograft for the closure of excised full-thickness burns.

Prompt and permanent closure of excised full-thickness burns remains a critical factor in a patient's recovery from massive burn injuries. Hypothetically, Integra Artificial Skin (Integra) may replace the need for allografts for immediate wound coverage, and cultured skin substitutes (CSS) that contain stratified epithelium may replace the need for autografts for definitive wound closure. To test this hypothesis, 3 patients with full-thickness burns of greater than 60% of their total body surface areas had their eschar excised within 14 days of admission. Integra was applied, and a skin biopsy was collected from each patient for the preparation of CSS. At 3 weeks or more after the application of the Integra and the collection of skin biopsies, the outer silastic cover of the Integra was removed and CSS were grafted. The CSS were irrigated with nutrients and antimicrobials for 6 days and then dressed with antimicrobial ointment and cotton gauze. Treated wounds were traced on days 14 and 28 after the grafting of CSS for determination of engraftment and wound closure, respectively. Cost analysis was not performed. Engraftment on postoperative day (POD) 14 was 98%+/-1% (mean +/- standard error of the mean), the ratio of closed:donor areas on POD 28 was 52.3+/-5.2, and no treated sites required regrafting. The histology of the closed wounds showed stable epithelium that covered a layer of newly formed fibrovascular tissue above the reticulated structure of the degrading Integra. The clinical outcomes of the closed wounds after POD 28 demonstrated smooth, pliable, and hypopigmented skin. Two patients who had received CSS grafts over Integra on their backs were positioned supine on air beds from POD 8 or POD 9 with minimal graft loss because of mechanical loading. One patient with a full-thickness burn of 88% of the total body surface area was covered definitively at 55 days postburn. These results demonstrate that the combination of CSS and Integra can accomplish functionally stable and cosmetically acceptable wound closure in patients with extensive full-thickness burns. This combination of alternatives to the conventional grafting of split-thickness skin permits the substitution of cadaveric allograft with Integra and the substitution of donor autograft with CSS. This approach to the closure of excised full-thickness burns is expected to reduce greatly the time to definitive closure of burn wounds and to reduce the morbidity associated with the harvesting of donor sites for split-thickness skin autografts.

Biocompatible Materials↗
PubMed2006

Assessment of the skin irritation potential of chemicals by using the SkinEthic reconstructed human epidermal model and the common skin irritation protocol evaluated in the ECVAM skin irritation validation study.

Currently, two reconstructed human skin models, EpiDerm and EPISKIN are being evaluated in an ECVAM skin irritation validation study. A common skin irritation protocol has been developed, differing only in minor technical details for the two models. A small-scale study, applying this common skin irritation protocol to the SkinEthic reconstructed human epidermis (RHE), was performed at ZEBET at the BfR, Berlin, Germany, to consider whether this protocol could be successfully transferred to another epidermal model. Twenty substances from Phase III of the ECVAM prevalidation study on skin irritation were tested with the SkinEthic RHE. After minor, model-specific adaptations for the SkinEthic RHE, almost identical results to those obtained with the EpiDerm and EPISKIN models were achieved. The overall accuracy of the method was more than 80%, indicating a reliable prediction of the skin irritation potential of the tested chemicals when compared to in vivo rabbit data. As a next step, inter laboratory reproducibility was assessed in a study conducted between ZEBET and the Department of Experimental Toxicology, Schering AG, Berlin, Germany. Six coded substances were tested in both laboratories, with three different batches of the SkinEthic model. The assay results showed good reproducibility and correct predictions of the skin irritation potential for all six test chemicals. The results obtained with the SkinEthic RHE and the common protocol were reproducible in both phases, and the overall outcome is very similar to that of earlier studies with the EPISKIN and EpiDerm models. Therefore, the SkinEthic skin irritation assay test protocol can now be evaluated in a formal "catch-up" validation study.

Cells, Cultured↗
PubMed2003

Study of active substances involved in skin dysfunction induced by crowding stress. I. Effect of crowding and isolation on some physiological variables, skin function and skin blood perfusion in hairless mice.

The effects of five levels of population density on various organs, the neuroendocrine system, skin function, skin blood perfusion, and blood parameters were studied in the hairless mouse. Skin barrier recovery was evaluated by measuring transepidermal water loss after tape stripping. Blood perfusion was measured by means of a laser Doppler imaging technique. The effect of a parasympathetic nerve stimulator, carpronium chloride, on skin function in the crowded animal model was also examined. A 7 d crowding (10, 15, 20 mice/cage) significantly increased the levels of corticosterone, catecholamines (norepinephrine, epinephrine and dopamine), glucose and serum lactate dehydrogenase activity in circulating blood, induced atrophy of kidney, ovary and thymus and hypertrophy of adrenal glands, and decreased body weight gain in comparison with the control (5 mice/cage). Crowding also increased epidermal thickness and epidermal proliferative activity, and decreased corneocyte size, rate of barrier recovery and skin blood perfusion. Most of these changes became more marked with increasing population density and/or longer exposure to a crowded environment. Isolation (1 mouse/cage) increased the level of norepinephrine and rate of skin blood perfusion, and significantly delayed barrier recovery. Repeated topical applications of carpronium chloride for 7 d improved the changes in skin blood perfusion, barrier recovery, kidney and ovary, and epidermal morphology induced by crowding. The crowded animal model could be useful for quantifying objectively the influence of crowded environment-induced stress on cutaneous function and blood perfusion.

Animals↗
PubMed1996

[Dermatotoxicity studies of calcipotriol (MC903) ointment--primary skin irritation, skin sensitization, phototoxicity and skin photosensitization].

MC903 ointment was studied on primary skin irritation in rabbits and skin sensitization, skin photosensitization and phototoxicity in guinea-pigs. 1. MC903 ointment, ointment base and deteriorated MC903 ointment induced erythematous changes in rabbit skin. These erythematous changes were not so serious, and they were classified as a mild irritant. 2. MC903 ointment was almost negative in skin sensitization study. 3. MC903 ointment has no skin phototoxicity in guinea-pigs. 4. MC903 ointment has no skin photosensitizing activity in guinea-pigs.

Animals↗
PubMed1977

Simultaneously obtained skin-puncture serum, skin-puncture plasma, and venous serum compared, and effects of warming the skin before puncture.

Specimens of skin-puncture serum and plasma and venous serum were simultaneously obtained from healthy adults and in each specimen the concentrations of 12 chemical constituents were measured. No clinically important difference was found in the concentrations of the constituents measured in skin-puncture serum and plasma with or without warming the skin before puncture. When the concentration of each of the measured constituents was compared in skin-puncture specimens and venous serum there were important differences in the concentrations of glucose, potassium, total protein, and calcium. Except for glucose, the concentrations of these were higher in venous serum. The degree of hemolysis was the same in skin-puncture serum and plasma, but less in venous serum. The greater hemolysis in skin-puncture specimens was not reflected in a clinically important increase in the values of lactate dehydrogenase and potassium. We conclude that there is a difference in the concentration of some chemical constituents in skin-puncture specimens and venous serum and that these differences should be considered when results for these types of specimens are compared.

Adult↗
PubMed1981

Suction skin blister, skin window, and skin chamber techniques to determine extravascular passage of cefotaxime in humans.

We report the results obtained in comparative study on the extravascular passage of cefotaxime, employing three different methods: suction skin blister, skin window, and skin chamber. Applying the skin blister method in two different ways, we also studied the influence that suction pressure and time lapse between blister formation and antibiotic injection had on the results obtained in order to standardize the method and establish repeatability of the results. Using the skin chamber method, we studied the influence that the different protein contents in the fluid used to fill the skin chamber had on extravascular concentrations.

Adolescent↗
PubMed2003

Liposomes increase skin penetration of entrapped and non-entrapped hydrophilic substances into human skin: a skin penetration and confocal laser scanning microscopy study.

Liposomes have been extensively studied and suggested as a vehicle for topical drug delivery systems. However, the mechanism by which liposomes deliver drugs into intact skin is not fully understood. In the present study, we have tried to understand the mechanism of transport of hydrophilic drugs into the skin using liposomes. The effect of separation of the non-entrapped, hydrophilic fluorescent compound, carboxyfluorescein (CF), from liposomally entrapped CF was investigated by measuring the penetration of CF across human skin under non-occlusive conditions in vitro using Franz diffusion cells. The fluorescent dye, CF, was incorporated into the liposomes and applied onto the skin. After a 6 and 12h incubation period, the amount of CF in the epidermal membrane and the full thickness skin was determined by fluorescence spectroscopy or by confocal laser scanning microscopy (CLSM). The liposomal formulation containing CF both inside and outside the vesicles showed statistically enhanced penetration of CF into the human stratum corneum (SC) as compared to the formulations containing CF only outside of the liposomes and CF in Tris buffer. The CLSM results revealed that the formulation in which CF was present outside the liposomes showed bright fluorescence intensity in the SC and very weak fluorescence in the viable epidermis. However, the CF in Tris buffer failed to show any fluorescence in the viable epidermis. The results indicated that phospholipid vesicles not only carry the entrapped hydrophilic substance, but also the non-entrapped hydrophilic substance into the SC and possibly into the deeper layers of the skin.

Diffusion Chambers, Culture↗
PubMed2006

Skin retinoid concentrations are modulated by CYP26AI expression restricted to basal keratinocytes in normal human skin and differentiated 3D skin models.

Cellular levels of all-trans retinoic acid (RA) are meticulously regulated utilizing an array of systems to balance uptake, biosynthesis, catabolism, and efflux transport. Metabolic transformation of all-trans RA to 4-hydroxylated RA appears to be primarily catalyzed by the cytochrome P450 (CYP) 26AI. Analysis of monolayer cultures of normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts by quantitative real-time PCR and reverse transcription-PCR revealed no basal levels of CYP26AI mRNA expression, whereas specific transcripts were detectable following addition of 10(-6) M all-trans RA. Immunofluorescence and Western blot analysis showed a weak expression of CYP26AI in NHEK, which was increased by stimulation with all-trans RA. Using a newly developed peptide antibody, we further examined the localization of CYP26AI expression in normal skin and three-dimensional (3D) skin models. In contrast to cell culture monolayers where CYP26AI was only weakly detectable, strong constitutive expression of CYP26AI in vivo and in organotypic culture was found to be restricted to basal epidermal keratinocytes, as well as eccrine sweat glands and sebaceous glands. These studies verify the capacity of human skin to metabolize RA, although substantial differences exist in CYP expression between normal skin and 3D skin models compared to monolayer cultures. Complex metabolic processes that maintain retinoid homeostasis may therefore be better studied in model systems more closely resembling in vivo skin. In light of our prior studies documenting the functional activity of RA metabolites, expression of CYP26 in the sebaceous gland epithelium supports the suggestion that altered RA metabolism may be involved in the pathogenesis of acne.

Blotting, Western↗
PubMed2005

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed in normal skin and cutaneous inflammatory diseases, but not in chronically UV-exposed skin and non-melanoma skin cancer.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a member of the tumor necrosis factor family that preferentially induces apoptosis in transformed but not normal cells and that is constitutively expressed in many organs including the skin. In addition to its therapeutic potential, TRAIL might act as a natural guardian eliminating transformed cells at an early stage. Ultraviolet (UV) radiation is not only a potent carcinogen because of its mutagenic effects but also because of its capacity to paralyze natural protection mechanisms, including the tumor suppressor gene p53. Therefore, we studied the effect of UV exposure on the expression of TRAIL in the skin by immunohistochemical analysis. TRAIL and its receptors TRAIL-R1 and TRAIL-R4 were constitutively expressed in normal epidermis and not altered in a variety of inflammatory dermatoses including those associated with interface dermatitis. TRAIL was not altered in biopsies of acute sunburn, polymorphic light eruption, and photoprovocation testing, indicating that acute UV exposure does not affect TRAIL expression. No differences were observed in UV-protected and chronically UV-exposed skin samples of younger adults. In contrast, TRAIL was significantly reduced in chronically UV-exposed skin of elderly individuals. In addition, TRAIL expression was reduced in actinic keratoses and Bowen disease and almost completely lost in basal cell and squamous cell carcinomas. In contrast, keratoacanthomas did not reveal any alterations in TRAIL expression. Taken together, these data indicate that chronic UV exposure in elderly patients results in the loss of TRAIL expression, which might contribute to the increased risk of skin cancer in this population. Down-regulation of TRAIL might represent another example of a natural protection mechanism that is eliminated by chronic UV exposure.

Adult↗
PubMed1993

Migration of Langerhans cells into human epidermis of "reconstructed" skin, normal skin, or healing skin, after grafting onto the nude mouse.

Human skin equivalents composed of keratinocytes cultured on a lattice constituted of human fibroblasts embedded in type I collagen were grafted onto the nude mouse. It is demonstrated, by indirect immunofluorescence and electron microscopy, that, after grafting, mouse Langerhans cells migrate into the human epidermis. Human Langerhans cells are not present in this system. In split-thickness human skin grafts, at long periods (5 and 12 months) after transplantation, a progressive migration of murine Ia(+) cells in the human epidermis and the presence of human Langerhans cells were shown by indirect immunofluorescence. Creation of a wound at the center of the grafted human skin and identification of the Langerhans cell origin shows a repopulation with human Langerhans cells provided the injury was performed early (2 months) after grafting. Injury at a later stage (5 months) resulted in presence of both human and murine Langerhans cells. These observations show 1) that, after grafting of "reconstructed" human skin or of split-thickness human skin onto nude mice, mouse Langerhans cells migrate into the grafted human epidermis; and 2) that the Langerhans cells repopulating a healing grafted epidermis devoid of Langerhans cells derived from the non-injured surrounding epidermis. The present work thus shows that besides bone marrow, lymph nodes, or/and spleen, surrounding cutaneous regions can also serve as sources of Langerhans cells.

Animals↗
PubMed1975

Multiple sequential skin cancers. The risk of skin cancer in patients with previous skin cancer.

We reviewed all reports of skin biopsies that had been performed at the Miami Veterans Administration Hospital within a three-year period. A total of 1,115 biopsy specimens of basal cell and squamous cell carcinomas were identified for 558 patients. Patient names, diagnosis, and dates of biopsies were tabulated for computer analysis. We determined that 121 patients (22%) developed at least one new or recurrent skin cancer during the average follow-up period of 1 1/2 years. From a computer review of clinic appointments, we determined that half of the 558 patients were unavailable for follow-up during that three-year period. Thus, the true rate of new and recurrent skin cancer in patients who had at least one skin cancer is no less than 22% and may approach 50% in the first 18 months. This high rate of new occurrences and recurrences of basal cell and squamous cell carcinomas emphasizes the need for repeated examinations of all patients with a history of skin cancer.

Basal Cell Carcinoma↗
PubMed2004

Complicated infections of skin and skin structures: when the infection is more than skin deep.

Skin and skin-structure infections are common, and range from minor pyodermas to severe necrotizing infections. Complicated infections are defined as involving abnormal skin or wounds, occurring in compromised hosts, or requiring surgical intervention. Classification schemes for these infections are varied and confusing. Distinguishing characteristics include the aetiological agent(s), clinical context and findings, depth of tissue involvement and rate of progression. The most common pathogens are aerobic Gram-positive cocci, but complicated infections frequently involve Gram-negative bacilli and anaerobic bacteria. Initial antibiotic therapy is usually empirical, and later modified by the results of stains and cultures of wound specimens. Broad-spectrum coverage is frequently needed for complicated infections. Ertapenem is a once-a-day parenteral Group 1 carbapenem antibiotic, recently licensed in the USA and Europe, which may assume an important role in treating some complicated skin and skin-structure infections. Surgical debridement is important for many complicated infections, and is the critical element in managing necrotizing fasciitis and myonecrosis.

Adult↗
PubMed1990

Formation of DNA adducts in the skin of psoriasis patients, in human skin in organ culture, and in mouse skin and lung following topical application of coal-tar and juniper tar.

Preparations of coal-tar and juniper tar (cade oil) that are used in the treatment of psoriasis are known to contain numerous potentially carcinogenic polycyclic aromatic hydrocarbons (PAH). Evidence of covalent binding to DNA by components of these mixtures was sought in a) human skin biopsy samples from 12 psoriasis patients receiving therapy with these agents, b) human skin explants maintained in organ culture and treated topically with the tars, and c) the skin and lungs of mice treated with repeated doses of the formulations following the regimen used in the clinic. DNA was isolated from the human and mouse tissues and digested enzymically to mononucleotides. 32P-Post-labeling analysis revealed the presence of aromatic DNA adducts in the biopsy samples at levels of up to 0.4 fmol total adducts/microgram DNA. Treatment of human skin in organ culture produced similar levels of adducts, while treatment with dithranol, a non-mutagenic therapeutic agent, resulted in chromatograms indistinguishable from those from untreated controls. In mouse skin, coal-tar ointment and juniper tar gave similar DNA adduct levels, with a similar time-course of removal: maximum levels (0.5 fmol/microgram DNA) at 24 h after the final treatment declined rapidly to 0.05 fmol/microgram at 7 d, thereafter declining slowly over the succeeding 25 d. However, while coal-tar ointment produced only very low levels of adducts in mouse lung (less than 0.03 fmol/microgram DNA), juniper tar produced adducts at a high level (0.7 fmol/microgram DNA) that were persistent in this tissue. These results provide direct evidence for the formation of potentially carcinogenic DNA damage in human and mouse tissue by components of these therapeutic tar preparations.

Administration, Topical↗
PubMed1990

Induction of eczematous skin reaction in experimentally induced hyperplastic skin of Balb/C mice by monoclonal anti-DNP IgE antibody: possible implications for skin lesion formation in atopic dermatitis.

Biphasic skin reaction with peak response at 1 and 24 h with prominent mast cell degranulation was induced by intravenous application of a monoclonal anti-DNP IgE antibody and subsequent skin test. This reaction was hapten-specific and mast-cell-dependent because no reaction was observed when oxasolone was used as an elicitation antigen or skin test was elicited in genetically mast-cell-deficient mice (W/Wvv). A partial spongiotic reaction and mononuclear cell infiltration into the epidermis were observed in mice with hyperplastic epidermis induced by topical retinoic acid. Cotransfer of DNFB-sensitized lymph node cells with anti-DNP IgE antibodies failed to enhance the skin test reaction in unsensitized mice. These results suggest that, to some degree, IgE antibody may play some role in the development of eczematous skin lesions in the rodent system without the involvement of cellular hypersensitivity.

Animals↗