Topical bioavailability of triamcinolone acetonide: effect of occlusion.

BACKGROUND/AIMS: Occlusion by covering the skin with an impermeable wrap enhances skin hydration, affects drug absorption and can induce the formation of a drug reservoir within the stratum corneum. This is desired in local therapy with topical corticosteroids. The aim of the study was to investigate the effect of occlusion before (experiment 1) and after (experiment 2) application on the penetration of triamcinolone acetonide (TACA) into the stratum corneum. METHODS: The experiments were conducted on the forearms of 10 healthy volunteers. In experiment 1, 100 microg/cm(2) TACA in acetone were applied on 3 sites per arm, one arm having been pre-occluded for 16 h. In experiment 2, the same dose was applied on 2 sites per arm, and one arm was occluded after application until skin sampling. Stratum corneum samples were removed by tape stripping at 0.5, 4 and 24 h (experiment 1) and 4 and 24 h (experiment 2) after application. Corneocytes and TACA were quantified by ultraviolet-visible spectroscopy and HPLC, respectively. The total TACA amount penetrated into the stratum corneum was evaluated by multifactor ANOVA. RESULTS: TACA penetration into the stratum corneum with and without pre-occlusion (experiment 1) showed no significant difference and decreased with time. Occlusion after application (experiment 2) produced a marked TACA accumulation within the stratum corneum, which persisted for 24 h. CONCLUSION: Pre-occlusion showed no effect on the topical bioavailability of TACA in the stratum corneum. In contrast, post-occlusion enhanced the TACA penetration by a factor of 2, favouring the development of a drug reservoir.

Mu-opiate receptor and Beta-endorphin expression in nerve endings and keratinocytes in human skin.

We have previously shown that human epidermal keratinocytes express a functionally active micro-opiate receptor, which adds a new dimension to the recently developed research in neuroimmunodermatology and neurogenic inflammation in skin diseases. Human keratinocytes specifically bind and also produce beta-endorphin, the endogenous micro-opiate receptor ligand. Using confocal imaging microscopy, we could now demonstrate that micro-opiate receptors are not only expressed in keratinocytes, but also on unmyelinated peripheral nerve fibers in the dermis and epidermis. Some of the peripheral nerve fibers also express the ligand beta-endorphin. The keratinocytes positive for beta-endorphin staining are clustered around the terminal ends of the unmyelinated nerve fibers. Therefore the opiate receptor system seems to be crucial in the direct communication between nerves and skin. The keratinocytes can influence the unmyelinated nerve fibers in the epidermis directly via secreting beta-endorphin. On the other hand, nerve fibers can also secrete beta-endorphin and influence the migration, differentiation and probably also the cytokine production pattern of keratinocytes.

Different expression of mu-opiate receptor in chronic and acute wounds and the effect of beta-endorphin on transforming growth factor beta type II receptor and cytokeratin 16 expression.

There is evidence that neuropeptides, especially the opiate receptor agonists, are involved in wound healing. We have previously observed that beta-endorphin, the endogenous ligand for the mu-opiate receptor, stimulates the expression of cytokeratin 16 in a dose-dependent manner in human skin organ cultures. Cytokeratin 16 is expressed in hyperproliferative epidermis such as psoriasis and wound healing. Therefore we were interested to study whether epidermal mu-opiate receptor expression is changed at the wound margins in acute and chronic wounds. Using classical and confocal microscopy, we were able to compare the expression level of mu-opiate receptors and the influence of beta-endorphin on transforming growth factor beta type II receptor in organ culture. Our results show indeed a significantly decreased expression of mu-opiate receptors on keratinocytes close to the wound margin of chronic wounds compared to acute wounds. Additionally beta-endorphin upregulates the expression of transforming growth factor beta type II receptor in human skin organ cultures. These results suggest a crucial role of opioid peptides not only in pain control but also in wound healing. Opioid peptides have already been used in animal models in treatment of wounds; they induce fibroblast proliferation and growth of capillaries, and accelerate the maturation of granulation tissue and the epithelization of the defect. Furthermore opioid peptides may fine-tune pain and the inflammatory response while healing takes place. This new knowledge could potentially be used to design new locally applied drugs to improve the healing of painful chronic wounds.

[Oral pemphigus vulgaris. Successful treatment with minocycline and nicotinamide]. / Enoraler Pemphigus vulgaris Erfolgreiche Monotherapie mit Minocyclin und Nicotinamid.

Minocycline is another possible alternative therapy for pemphigus vulgaris. We successfully treated a Jewish patient with oral pemphigus vulgaris with with minocycline and nicotinamide. Minocycline may be a useful second-line drug for therapy- resistant cases of pemphigus vulgaris.

Clustering of bloodstream infections during maggot debridement therapy using contaminated larvae of Protophormia terraenovae.

BACKGROUND: The treatment of human wounds with fly larvae is an ancient procedure recently reintroduced into medical practice under the term of biosurgery. The crucial technical problem of biosurgery is asepsis of the larvae. PATIENTS AND METHODS: Since February 1999, we conducted a prospective observational study on the use of maggot debridement therapy in the management of ulcers refractory to standard treatment. RESULTS: During the first 5 months we observed five bloodstream infections (four with Providencia stuartii and one with Candida albicans) in 24 patients (21%) treated with maggots. The blood isolates could be traced back to contaminated maggots. Accordingly, the disinfecting procedure of the maggots was optimized and the fly species was changed from Protophormia terraenovae to Phaenicia (Lucilia) sericata. With the new procedure, no case of sepsis occurred in 45 patients treated between January 2000 and December 2001 (p < 0.005). CONCLUSION: Despite promising benefits, maggot debridement therapy can be threatened by serious infectious complications. With an appropriate disinfecting procedure, maggots free of pathogens can be obtained. Provided the maggots have been effectively disinfected, their application on chronic ulcers seems to be safe.

[Telemedicine: perspectives and multidisciplinary approach]. / Télémédecine: perspectives et approche pluridisciplinaire.

BACKGROUND: Telemedicine is use of the new computer-based communication technologies for medical purposes. It augments the exchange of scientific information, while its applications in the fields of patient care and medical education cover remote diagnosis and therapy as well as remote education and training. METHOD: This article reviews the development of telemedicine and its application to specialties such as anaesthesiology, dermatology, medicine, surgery and pathology at the University Hospital of Basle, Switzerland. RESULTS: Since 1980 the Department of Medicine has held multidisciplinary teleconferences for expert consultation and medical education. Since 1992 the Institute of Pathology has been linked to remote hospitals for real-time biopsy, and, since 1997, remote dermato-histopathological diagnosis has been performed in conjunction with a number of centres and practitioners. International academic teleconferences have been held in the field of surgery since 1986 and there is an interactive education programme via telemedicine in the field of anaesthesiology. The technology in use must be adapted to needs: since few practitioners are currently connected to the Internet, teleconferencing will still be the rule in the Department of Medicine. Remote diagnosis in dermatology and pathology requires high-resolution images transmitted by self-developed software via 64 Kb/s ISDN connection, while surgery works with ISDN teleconferencing at 384 Kb/s to ensure live transmission of surgical procedures with high-quality images. CONCLUSION: Our practice, based on several hundred cases, suggests that telemedicine is useful in simplifying and expanding access to remote interdisciplinary expertise, as well as improving medical education in a number of specialties. Telemedicine's multidisciplinary approach is to be recommended.

beta-endorphin stimulates cytokeratin 16 expression and downregulates mu-opiate receptor expression in human epidermis.

It has been reported that opioid peptides modulate the differentiation of normal human keratinocytes and that mu-opiate receptors are expressed in human epidermis. The regulation of keratinocyte differentiation is particularly important in psoriasis, and one of the markers for hyperproliferative and differentiating skin diseases is cytokeratin 16. The finding that the endogenous mu-opiate receptor ligand beta-endorphin is increased in serum of patients with psoriasis indicates that the mu-opiate system may play an important role in the pathophysiology of the skin. In this study, we addressed the question whether there is a link between mu-opiate receptor regulation and cytokeratin 16 expression in normal and psoriatic skin. Firstly, we demonstrate that beta-endorphin concentrations between 16 and 1000 nM significantly downregulate mu-opiate receptor expression in epidermis of cultured human skin after 48 h. Secondly, we show that beta-endorphin regulates cytokeratin 16 expression in the epidermis of skin organ cultures exposed to 41-125 nM beta-endorphin for 48 h, leading to elevated cytokeratin 16 production. As expected, the expression of cytokeratin 16 was detected primarily in the suprabasal layer. The same pattern was observed in psoriatic lesional skin, i.e., mu-opiate receptor expression was significantly downregulated and cytokeratin 16 expression upregulated. These results suggest that the mu-opiate receptor system and its ligand beta-endorphin are involved in the pathogenesis of psoriasis, especially in terms of differentiation.

[Treatment of scabies with special consideration of the approach in infancy, pregnancy and while nursing]. / Die Skabiestherapie unter besonderer Berücksichtigung des frühen Kindesalters, der Schwangerschaft und Stillzeit.

Infestation of human skin with scabies mites remains an persistent problem in daily dermatological practice. There are several therapeutic regiments against scabies which have been proven effective and without major side effects. Because of known neurotoxicity of lindane as well as intoxication/problems following systemic absorption of benzyl alcohol (the metabolite of benzyl benzoate), these two compounds have to be considered with caution in early childhood scabies as well as during pregnancy and nursing. The pharmacology and spectrum of clinical side effects of the approved anti-scabies preparations (lindane, benzyl benzoate, crotamiton) as well as permethrin (not available in Germany) are reviewed.

Is there a relation between risk groups or initial CD4 T cell counts and prevalence of seborrheic dermatitis in HIV-infected patients?

OBJECTIVES: (i) To investigate whether there is a difference in the prevalence of seborrheic dermatitis (SD) between homo- or bisexual HIV-infected patients and HIV-infected intravenous drug users, (ii) to study whether the initial CD4 T cell count at the first positive HIV test is of any significance for the prevalence of SD and furthermore to analyze whether (iii) antiretroviral treatment influences the prevalence and time course of SD. PATIENTS AND METHODS: Since 1992 we have been following, within the scope of the Swiss HIV Cohort Study, a group of individuals with proven HIV infection. In this study all HIV-infected patients belonging either to the risk group of homo- or bisexuals or that of intravenous drug users were included for further analysis. RESULTS: We included 226 men and 51 women. The ages ranged from 17 to 68 years (mean 30.1). One hundred and forty-four were homo- or bisexual men and 133 (82 men and 51 women) were intravenous drug users. Out of these 277 HIV-infected patients, 66 (23.8%) had SD at baseline and 7 (2.5%) developed SD during the observation period (male:female = 68:5). CONCLUSION: In our study we found that (i) the risk group influences the prevalence and time course of SD, yet that (ii) neither the initial CD4 T cell count nor (iii) antiretroviral treatment is of any significance.

Percutaneous absorption of salicylic acid in man after topical administration of three different formulations.

OBJECTIVE: To determine the amount of drug which is absorbed during 1 day following topical application of three different preparations containing salicylic acid. METHODS: Ten grams of the formulations, either (a) Kerasaltrade mark 5% ointment, (b) salicylic acid 5% or (c) 10% in petrolatum, were administered consecutively to a 600-cm2 area on alternating sides of the back of healthy volunteers (n = 9). Thirty minutes after application, a skin area of 2.54 cm2 was stripped with D-Squametrade mark adhesive disks to determine the amount of salicylic acid in the stratum corneum. The entire application site was then covered by a thin gauze bandage and was not washed for the next 24 h. Urine was collected for 26 h following administration, hydrolyzed and assayed by HPLC analysis. RESULTS: The absolute amounts absorbed and excreted were 52.6 +/- 29.4 mg (mean +/- SD), 127.1 +/- 43.9 mg and 208.0 +/- 81.7 mg, and the doses absorbed in relation to the doses applied (500 mg salicylic acid in case of formulations a and b and 1,000 mg for formulation c) were 9.3 +/- 3.8, 25.1 +/- 8.5 and 20.2 +/- 7.7%, respectively. The amounts of salicylic acid in the skin 30 min after application were 36.3 +/- 16.5, 18.2 +/- 11.9 and 31.3 +/- 15.4 microg/ cm2 as determined by the tape stripping procedure. CONCLUSIONS: Significant differences in the doses absorbed were detected between the two formulations a and b (same concentration) with different vehicles (p value < 0.001) as well as between b and c (same vehicle) with different concentrations (p value = 0.018) using Student's paired t test. These results demonstrate that salicylic acid is well absorbed by healthy skin.

Expression of mu-opiate receptor in human epidermis and keratinocytes.

There is increasing evidence that neurotransmitters play a crucial role in skin physiology and pathology. The expression and production of proopiomelanocortin molecules such as beta-endorphin in human epidermis suggest that an opiate receptor is present in keratinocytes. In this paper we show that human epidermal keratinocytes express a mu-opiate receptor on both the mRNA level and the protein level. Performing polymerase chain reaction with cDNA libraries from human epidermal keratinocytes gave the polymerase chain reaction products of the expected length, which were confirmed as mu-opiate receptors by Southern blot analysis. Using in situ hybridization techniques with a specific probe for mu-opiate receptors we detected the receptor in human epidermis. There was a cytoplasmic expression in all layers of the epidermis, which was more distinct in the suprabasal layers. Immunohistochemistry using the mu-opiate receptor-specific antibody indicates that epidermis expresses protein as well, and that the protein level is more elevated in the basal layer. The correlation between the locations of both mRNA and protein expression in skin indicates that the mu-opiate receptor has not only been transcribed but also has a specific function. To prove a function of the receptor we performed a functional assay using skin organ cultures from human skin transplants. After 48 h incubation with Naloxone or beta-endorphin the expression of the mu-opiate receptor in epidermis was significantly downregulated compared with the control. These results show that a functional receptor indeed exists in human epidermis.

[Epidemiology of skin diseases in HIV-infected patients: a prospective cohort study]. / Epidemiologie von Hauterkrankungen bei HIV-infizierten Patienten: eine prospektive Kohortenstudie.

Along with the rising AIDS epidemic, the recognition of mucocutaneous lesions indicating HIV infection is important not only for dermatologists but also for general practitioners. During 36 months we prospectively followed 357 HIV-1-infected patients on a regular base, and all the dermatologic findings were evaluated statistically. Several skin problems such as seborrheic dermatitis, may occur early in HIV infection. Mollusca contagiosa, oral hairy leukoplakia and Kaposi's sarcoma are often clinical signs of marked disease progression with very low CD4-cell counts.

In situ analysis of transforming growth factors-beta (TGF-beta 1, TGF-beta 2, TGF-beta 3) and TGF-beta type II receptor expression in basal cell carcinomas.

Transforming growth factor-beta (TGF-beta) consists of a highly homologous family of multifunctional peptides which are differentially expressed and function in a wide range of target cells. Aberrant expressions of TGF-beta s have been implicated in a number of disease processes, particularly those involving fibrotic and inflammatory lesions, and loss of TGF-beta growth inhibition may play a part in the progression of certain neoplasms. In the present study, we have analysed and compared, by in situ hybridization, mRNA expression of transforming growth factors-beta (TGF-beta 1, TGF-beta 2, TGF-beta 3) and TGF-beta type II receptor (T beta R II), and, by immunohistochemistry, the distribution of TGF-beta 3 protein in normal human skin and in basal cell carcinoma (BCC). The stroma of most BCCs revealed enhanced TGF-beta 1 and T beta R II mRNA expression when compared with normal dermis. A minority of BCCs also showed stromal overexpression of TGF-beta 2 and/or TGF-beta 3 mRNA. However, tumour tissues of all BCCs revealed weaker TGF-beta 3 mRNA and protein expression than normal interfollicular epidermis and hair follicle epithelia, whereas expression of TGF-beta 1 mRNA was comparably weak in tumour tissues and normal skin epithelia. Expression of TGF-beta 2 mRNA, which was clearly detectable in distinct hair follicle epithelia, was only barely detectable in normal interfollicular epidermis and in tumour tissues. In contrast, abundant T beta R II mRNA expression was observed both in normal skin epithelia and tumour tissues. From these findings, we suggest that increased stromal TGF-beta activity induces fibrotic alterations which promote tumour survival and/or progression via paracrine mechanisms, whereas lack of TGF-beta 3 expression by tumour cells may contribute to an autocrine growth control defect in BCCs.

Delayed-type hypersensitivity to subcutaneous lidocaine with tolerance to articaine: confirmation by in vivo and in vitro tests.

A 43-year-old woman suffered from recurrent localized swellings and an eczematous dermatitis starting 1 day after an injection of lidocaine. Intradermal patch and lymphocyte transformation tests revealed sensitization to lidocaine and cross-reactivity to the other aminoacylamide local anesthetics bupivacaine, mepivacaine and prilocaine, but not to articane. Contact allergy to the ester local anesthetics benzocaine, procaine and tetracaine, the quinoline or aminoacylamide cinchocaine, and the preservatives methylparaben and metabisulfite, was excluded. A subcutaneous challenge with articaine was well tolerated.

[Skin manifestations of graft-versus-host reaction following bone marrow transplantation]. / Hautmanifestationen der Graft-versus-host-Reaktion nach Knochenmarktransplantation.

We review the cutaneous manifestations of acute and chronic graft versus host disease (GvHD). Acute GvHD is characterized by initial itching, pain on pressure and erythema which begins on posterior auricular skin, palms and soles. The disease evolves into a typical but nonspecific maculopapular rash. Confluent rashes and follicular erythema may occur. Erosive oral lesions usually develop. The most severe variant of GvHD is toxic epidermal necrolysis, which often has a fatal outcome. The onset of chronic GvHD usually occurs more than 100 days after bone marrow transplantation and may be preceded by the acute form. The spectrum of skin changes includes lichenoid pruritic lesions with violaceous color and scleroderma-like skin involvement. Investigation of unknown rashes in these patients includes skin biopsy, which clearly differentiates leukocytoclastic vasculitis and erythema exsudativum multiforme with lymphocytic vasculitis from cutaneous manifestations of GvHD. Special stains may reveal bacteria and fungus in septicemic patients. The therapeutic options are discussed.

[Lindane]. / Lindan.

In Europe and in the US ectoparasitic diseases are increasingly diagnosed in all classes of society. Modern means of transportation promote the spreading from endemic areas into new regions and therefore questions of therapy are becoming increasingly important. A series of preparations in various galenic formulations and in various concentrations are available to treat the ectoparasitic diseases. Due to reports on Lindane poisonings the clinical use of Lindane preparations for the treatment of scabies and pediculosis has become somewhat controversial. In this article we review older and more recent data on pharmacology, pharmacokinetics and toxicology of gamma-1,2,3,4,5,6-Hexachlorcyclohexan [Lindane]. It is pointed out that in the USA Lindane is offered in 1% preparations whereas in the German speaking Europe only 0.3% preparations are available. This latter concentration is considered as sufficient to treat the ectoparasitosis. Furthermore the use of this remedy and aspects of Lindane resistance are discussed. It is concluded that only through additional in depth education of the patients and their folks successful treatment is possible and intoxication can be prevented.

In situ analysis of transforming growth factor-beta s (TGF-beta 1, TGF-beta 2, TGF-beta 3), and TGF-beta type II receptor expression in malignant melanoma.

We have analysed, by in situ hybridization, mRNA expression of TGF-beta 1, TGF-beta 2, TGF-beta 3, and of TGF-beta type II receptor in benign melanocytic naevi, primary melanomas, and in skin metastases of malignant melanomas. Our results show that melanoma progression correlates with overexpression of TGF-beta. All skin metastases and most primary melanomas invasive to Clark's level IV-V revealed specific TGF-beta 2 mRNA and protein expression. However, expression of this cytokine was not observed in benign melanocytic lesions and was detected only in one of five early primary melanomas investigated. Some primary melanomas and skin metastases also revealed specific TGF-beta 1 mRNA signals although expression of this isoform was not found in benign naevi. TGF-beta 3 expression, which was only barely detectable in benign melanocytic lesions, was enhanced in some skin metastases. Interestingly, the epidermis overlaying melanomas revealed lower levels of TGF-beta 3 mRNA expression than epidermis of healthy skin or epidermis adjacent to benign naevi, thereby suggesting that paracrine mechanisms between tumour cells and keratinocytes may influence melanoma development. In primary melanomas TGF-beta type II receptor mRNA signals were much more heterogeneously distributed when compared to benign melanocytic naevi, suggesting variable degrees of TGF-beta resistance among melanoma cells within individual lesions. However, melanoma progression appeared not to be correlated with a complete loss of TGF-beta type II receptor gene expression, since all skin metastases revealed clearly detectable although heterogeneous levels of TGF-beta type II receptor mRNA expression.