Fungicidal activity plus reservoir effect allow short treatment courses with terbinafine in tinea pedis

Terbinafine, a synthetic allylamine, exerts fungicidal activity against dermatophytes, the causative pathogens of tinea pedis. As proven in numerous clinical trials, tinea pedis can be effectively and safely treated by topical terbinafine. In fact, a 1-week application of terbinafine 1% cream eradicated fungal pathogens at least as effectively as 4-week treatment courses with topical azole derivative antifungals and showed lower relapse rates. A new innovative single-application formulation of terbinafine 1% in a film-forming solution produces a high concentration gradient on the skin surface and enables a prolonged (up to 13 days) exposure of the skin to terbinafine. High drug penetration into the skin results in an otherwise not obtained drug reservoir in the horny layer, the location of dermatophytes in tinea pedis. Although azole antimycotics can also effectively penetrate into the horny layer of the skin, short-term therapy might not be feasible due to its primarily fungistatic activity against dermatophytes. Thus, we conclude that the high efficacy of short-term treatment with terbinafine in patients with tinea pedis is possible due to its fungicidal activity coupled with a distinct reservoir formation in the upper layers of the epidermis. Copyright (C) 2008 S. Karger AG, Basel

Innovative Agents for Actinic Keratosis and Nanocarriers Enhancing Skin Penetration

Actinic keratosis and cutaneous squamous cell carcinoma are of increasing importance with aging and increased ultraviolet light exposure in Western societies. Efficient and well-tolerated therapy is still a matter of concern. As with tumours of other organs, new target sites and innovative drugs selectively addressing them are widely looked for. Due to the relevance for DNA synthesis and thus cell proliferation, human DNA polymerase alpha should be such a target, the more so as the three-dimensional structure of the active site has been proposed based on the application of molecular modelling methods and molecular dynamics simulations. The modelled structure of the active site was used for docking nucleotide analogues in order to design selective inhibitors. Consequently, well-fitting thymidine and guanosine analogues were synthesized and tested in vitro for their influence on normal and transformed human keratinocytes. In fact, the combination of modelling studies and in vitro tests allowed us to design antiproliferative and cytotoxic agents which are new drug candidates for the therapy of skin tumours, given the agents are no relevant substrates of nucleotide transporters (MRP-4, MRP-5) expressed by skin cancer cells. Essential kinases for nucleoside activation were detected, too, corresponding with the observed effects of nucleoside analogues. Due to the rather high molecular weight and poor solubility, however, skin penetration should be poor and thus topical therapy may require carriers to improve the uptake. This becomes feasible by lipidic and non-lipidic nanoparticles which can enhance the uptake of lipophilic agents up to 13-fold. Copyright (C) 2010 S. Karger AG, Base

Glucocorticoids for human skin: New aspects of the mechanism of action

Topical glucocorticoids have always been considered first-line drugs for inflammatory diseases of the skin and bronchial system. Applied systemically, glucocorticoids are used for severe inflammatory and immunological diseases and the inhibition of transplant rejection. Owing to the progress in molecular pharmacology, the knowledge of the mechanism of action has increased during the last years. Besides distinct genomic targets, which are due to the activation of specific cytoplasmatic receptors resulting in the (trans-) activation or (trans-) repression of target genes, there are non-genomic effects on the basis of the interference with membrane-associated receptors as well as with membrane lipids. In fact, various glucocorticoids appear to differ with respect to the relative influence on these targets. Thus, the extended knowledge of glucocorticoid-induced cellular signalling should allow the design and development of even more specifically acting drugs-as it has been obtained with other steroids, e.g. estrogens for osteoporosis prevention. Copyright (C) 2005 S. Karger AG, Basel

Resistance of Liposomal Sunscreen Formulations against Plain Water as well as Salt Water Exposure and Perspiration

The present in vivo investigation using a total of 30 healthy adult volunteers with Fitzpatrick skin type II examines the persistent efficacy of sunscreens using liposomal suspensions as the vehicle. Based on the COLIPA guidelines, the protective effect of a single application of 4 different liposomal sunscreen formulations (sun protection factors, SPFs: 50+, 30,25 and 15) against sunburn at the recommended amount of 2 mg/cm(2) was determined after exposure of the skin to plain water and salt water and after profuse perspiration. Under the influence of plain water, salt water and sweating, the SPF values of sunscreen 1 (labeled SPF of 50+) were reduced only marginally to 97, 96 and 99%, respectively, those of sunscreen 2 (labeled SPF of 30) to 97, 96 and 99%, respectively, those of sunscreen 3 (labeled SPE of 25) to 90, 83 and 91%, respectively, and those of sunscreen 4 (labeled SPF of 15) to 96, 96 and 95%, respectively. This set of data shows that despite plain water and salt water immersion or profuse sweating, the liposomal sunscreen formulation may deliver a long-lasting protective effect in everyday situations encountered by outdoor workers or during leisure activities. Copyright (C) 2010 S. Karger AG, Base

The Phenion (R) Full-Thickness Skin Model for Percutaneous Absorption Testing

In recent years many efforts have been made to replace dermal toxicity testing of chemicals in the animal by in vitro assays. As a member of a German research consortium, we have previously contributed to the validation of an in vitro test protocol for percutaneous absorption studies on the basis of reconstructed human epidermis and both human and pig skin ex vivo. Aiming to assess the barrier properties of a newly developed reconstructed skin model, this protocol has now been transferred to the Phenion (R) Full-Thickness Skin Model (FT model). The permeation of testosterone and caffeine was quantified in parallel to that of pig skin using Franz-type diffusion cells. In addition, the permeation of benzoic acid and nicotine was studied. As expected, the FT model is more permeable than pig skin, yet its barrier properties are well in accordance with those of reconstructed human epidermis when compared to previous data. In fact, the FT model most efficiently retards testosterone as the compound of highest lipophilicity, which can be explained by an additional uptake by a reservoir formed by the dermis equivalent. Thus, the structure closely parallels human skin. In consequence, the Phenion FT model appears to be suitable for percutaneous absorption studies in hazard analysis and should be subjected to a catch-up validation study. Copyright (C) 2009 S. Karger AG, Base

Tetracycline Actions Relevant to Rosacea Treatment

Until today, the pathogenesis of rosacea is not known in detail. Yet in recent years evidence has been accumulating that rosacea with its common symptoms such as inflammatory lesions, erythema, telangiectasia, phymatous changes, and ocular symptoms is of inflammatory nature. Tetracycline derivatives like doxycycline successfully used in the treatment of skin diseases like acne and rosacea seem to inhibit different inflammatory pathways involved in the pathogenesis by various modes of action. Although data for skin diseases are relatively scanty, the following modes of action of tetracyclines seem to be most relevant for an effective treatment of acne and rosacea: inhibition of matrix metalloproteinases, downmodulation of cytokines, inhibition of cell movement and proliferation, inhibition of granuloma formation, inhibition of reactive oxygen species, nitric oxide, and angiogenesis, whereas inhibition of phospholipase A2 seems to be of lower importance. The role of the saprophytic mite Demodex folliculorum remains to be clarified. Additional studies are necessary to further elucidate how tetracyclines work in rosacea treatment. Copyright (C) 2009 S. Karger AG, Base

Morphine Metabolism in Human Skin Microsomes

For patients with severe skin wounds, topically applied morphine is an option to induce efficient analgesia due to the presence of opioid receptors in the skin. However, for topical administration it is important to know whether the substance is biotransformed in the skin as this can eventually reduce the concentration of the active agent considerably. We use skin microsomes to elucidate the impact of skin metabolism on the activity of topically applied morphine. We are able to demonstrate that morphine is only glucuronidated in traces, indicating that the biotransformation in the skin can be neglected when morphine is applied topically. Hence, there is no need to take biotransformation into account when setting up the treatment regimen. Copyright (C) 2012 S. Karger AG, Base

Late cutaneous schistosomiasis representing an isolated skin manifestation of Schistosoma mansoni infection

Ectopic late cutaneous schistosomiasis is usually preceded or accompanied by visceral schistosomiasis infection. Our patient presented the very rare case of late cutaneous schistosomiasis as an isolated skin manifestation. Perigenital lesions occurred 1 year after contact with infested water. Identification of the few eggs remaining in the late lesion among the dense cellular infiltrate was difficult. Electron-microscopic studies clearly demonstrated the characteristic eggshell ultrastructure. Copyright (C) 2000 S. Karger AG, Basel

Bioavailability, Antipsoriatic Efficacy and Tolerability of a New Light Cream with Mometasone Furoate 0.1%

Mometasone furoate, a potent glucocorticoid (class III) with a favorable benefit/risk ratio, has emerged as a standard medication for the treatment of inflammatory skin disorders. The purpose of the investigation presented here was to determine the noninferiority of a topical mometasone formulation, a light cream (O/W 60/40 emulsion) with mometasone furoate 0.1% (water content of 33%) versus marketed comparators. Using the vasoconstrictor assay, a strong blanching effect of the new cream (called Mometasone cream) comparable to that of a mometasone comparator, a fatty cream with mometasone furoate 0.1%, could be demonstrated. Thus, the topical bioavailability of the active ingredient mometasone furoate (0.1%) was regarded to be similar for Mometasone cream and the mometasone comparator. Using the psoriasis plaque test, a strong antipsoriatic effect comparable to that of the mometasone comparator was found for Mometasone cream after 12 days of occlusive treatment. A nearly identical reduction in the mean infiltrate thickness and similar mean AUC values were noted with both formulations confirmed by clinical assessment data. The noninferiority of Mometasone cream to its active comparator with re-spect to the AUC of change to baseline in infiltrate thickness was demonstrated. Both medications were well tolerated. Overall, Mometasone cream and the mometasone comparator showed similar efficacy and tolerability. Mometasone cream, in addition to its high potency and good tolerability, provides the properties of a light cream, which might make this new medication particularly suitable for application on acutely inflamed and sensitive skin. Copyright (C) 2012 S. Karger AG, Base