314 research outputs found
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
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
Ultraviolet B irradiation-induced keratinocyte senescence and impaired development of 3D epidermal reconstruct
Ultraviolet B (UVB) induces morphological and functional changes of the skin. This study investigated the effect of UVB on keratinocyte senescence and the development of reconstructed human epidermis (RHE). Primary normal human keratinocytes (NHK) from juvenile foreskin were irradiated with UVB (30 mJ cm–2) and these effects were compared to NHK that underwent senescence in the late passage. UVB enhanced the accumulation of reactive oxygen species (ROS) and halted cell replication as detected by BrdU cell proliferation assay. The senescence phenotype was evaluated by beta-galactosidase (β-gal) staining and qPCR of genes related to senescent regulation, i.e. p16INK4a, cyclin D2, and IFI27. Senescence induced by high dose UVB resulted in morphological changes, enhanced β-gal activity, elevated cellular ROS levels and reduced DNA synthesis. qPCR revealed differential expression of the genes regulated senescence. p16INK4a expression was significantly increased in NHK exposed to UVB whereas enhanced IFI27 expression was observed only in cultural senescence. The levels of cyclin D2 expression were not significantly altered either by UVB or long culturing conditions. UVB significantly induced the aging phenotype in keratinocytes and impaired epidermal development. RHE generated from UVB-irradiated keratinocytes showed a thinner cross-sectional structure and the majority of keratinocytes in the lower epidermis were degenerated. The 3D epidermis model is useful in studying the skin aging process
A Systematic Approach from a Comparison of Three Glucocorticoids
Solid lipid nanoparticles (SLNs) can enhance drug penetration into the skin,
yet the mechanism of the improved transport is not known in full. To unravel
the influence of the drug-particle interaction on penetration enhancement, 3
glucocorticoids (GCs), prednisolone (PD), the diester prednicarbate (PC) and
the monoester betamethasone 17-valerate (BMV), varying in structure and
lipophilicity, were loaded onto SLNs. Theoretical permeability coefficients
(cm/s) of the agents rank BMV (–6.38) ≧ PC (–6.57) > PD (–7.30). GC-particle
interaction, drug release and skin penetration were investigated including a
conventional oil-in-water cream for reference. Both with SLN and cream, PD
release was clearly superior to PC release which exceeded BMV release. With
the cream, the rank order did not change when studying skin penetration, and
skin penetration is thus predominantly influenced by drug release. Yet, the
penetration profile for the GCs loaded onto SLNs completely changed, and
differences between the steroids were almost lost. Thus, SLNs influence skin
penetration by an intrinsic mechanism linked to a specific interaction of the
drug-carrier complex and the skin surface, which becomes possible by the lipid
nature and nanosize of the carrier and appears not to be derived by testing
drug release. Interestingly, PC and PD uptake from SLN even resulted in
epidermal targeting. Thus, SLNs are not only able to improve skin penetration
of topically applied drugs, but may also be of particular interest when
specifically aiming to influence epidermal dysfunction
Fifty-kDa Hyaluronic Acid Upregulates Some Epidermal Genes without Changing TNF-α Expression in Reconstituted Epidermis
Background: Due to its strong water binding potential, hyaluronic acid (HA) is a well-known active ingredient for cosmetic applications. However, based on its varying molecular size, skin penetration of HA may be limited. Recent studies have demonstrated that low-molecular-weight HA (LMW HA) may show a certain proinflammatory activity. We thus aimed to characterize an LMW-sized HA molecule that combines strong anti-aging abilities with efficient skin penetration but lacks potential proinflammatory effects. Methods: Total RNA and total protein were isolated from reconstituted human epidermis following incubation with HAs of various molecular weights (20, 50, 130, 300, 800 and 1,500 kDa). Tumor necrosis factor-alpha expression was determined using quantitative PCR. Genonnic and proteomic expression of various junctional proteins was determined using Affymetrix and common Western blotting techniques. Results: LMW HA of approximately 50 kDa did not significantly alter tumor necrosis factor-alpha expression compared to 20-kDa HA, but revealed significantly higher skin penetration rates than larger sized HA associated with increased expression of genes and proteins known to be involved in tight junction formation and keratinocyte cohesion. Conclusion: LMW HA of approximately 50 kDa shows better penetration abilities than larger-sized HA. In addition, LMW HA influences the expression of various genes including those contributing to keratinocyte differentiation and formation of intercellular tight junction complexes without showing proinflammatory activity. These observations contribute to current knowledge on the effects of LMW HA on keratinocyte biology and cutaneous physiology. Copyright (C) 2011 S. Karger AG, Base
In vitro Efficacy of a Novel Guanosine-Analog Phosphonate
Actinic keratosis, a frequent carcinoma in situ of non-melanoma skin cancer
(NMSC), can transform into life-threatening cutaneous squamous cell carcinoma.
Current treatment is limited due to low complete clearance rates and asks for
novel therapeutic concepts; the novel purine nucleotide analogue OxBu may be
an option. In order to enhance skin penetration, solid lipid nanoparticles
(SLN, 136-156 nm) were produced with an OxBu entrapment efficiency of 96.5 ±
0.1%. For improved preclinical evaluation, we combined tissue engineering with
clinically used keratin-18 quantification. Three doses of 10-3 mol/l OxBu,
dissolved in phosphate-buffered saline as well as loaded to SLN, were
effective on reconstructed NMSC. Tumour response and apoptosis induction were
evaluated by an increase in caspase-cleaved fragment of keratin-18, caspase-7
activation as well as by reduced expression of matrix metallopeptidase-2 and
Ki-67. OxBu efficacy was superior to equimolar 5-fluorouracil solution, and
thus the drug should be subjected to the next step in preclinical evaluation
Data-based modeling of drug penetration relates human skin barrier function to the interplay of diffusivity and free-energy profiles
Based on experimental concentration depth profiles of the antiinflammatory drug dexamethasone in human skin, we model the time-dependent drug penetration by the 1D general diffusion equation that accounts for spatial variations in the diffusivity and free energy. For this, we numerically invert the diffusion equation and thereby obtain the diffusivity and the free-energy profiles of the drug as a function of skin depth without further model assumptions. As the only input, drug concentration profiles derived from X-ray microscopy at three consecutive times are used. For dexamethasone, skin barrier function is shown to rely on the combination of a substantially reduced drug diffusivity in the stratum corneum (the outermost epidermal layer), dominant at short times, and a pronounced free-energy barrier at the transition from the epidermis to the dermis underneath, which determines the drug distribution in the long-time limit. Our modeling approach, which is generally applicable to all kinds of barriers and diffusors, allows us to disentangle diffusivity from free-energetic effects. Thereby we can predict short-time drug penetration, where experimental measurements are not feasible, as well as long-time permeation, where ex vivo samples deteriorate, and thus span the entire timescales of biological barrier functioning
Efficacy of a Tyrothricin-Containing Wound Gel in an Abrasive Wound Model for Superficial Wounds
Background: Topical preparations are a common treatment for superficialacute wounds, which at the least do not interfere with healing andideally result in enhanced wound healing irrespective of microbialcolonization. Objective: To examine the effects of a topicalantimicrobial gel and its vehicle on the wound healing of standardized,superficial abrasions. Methods: Thirty-three healthy volunteers wereenrolled in a double-blinded, randomized, intraindividual comparisonstudy. Three standardized, superficial abrasions were induced on theirforearms. A tyrothricin 0.1% gel (Tyrosur (R) gel; EngelhardArzneimittel GmbH & Co. KG, Niederdorfelden, Germany) and its vehiclewere randomly applied to two of the test areas, and one lesion remaineduntreated. Results: A significant improvement of wound healing was seenwith both tyrothricin 0.1% gel and its corresponding vehicle in theclinical assessment. The mean area under the curve (AUC) of woundhealing scores was the same for both preparations and the meanreepithelization scores were comparable at all test points over theentire 12 days. A lower mean AUC representing less reepithelization wasfound for the untreated test fields. Conclusion: The use of tyrothricin0.1% gel and its corresponding vehicle resulted in statisticallysignificant improved wound healing with an earlier onset of healing inparticular. Based on these results obtained using an abrasive woundmodel, it can be concluded that the addition of tyrothricin 0.1% to thegel vehicle did not interfere with the improved wound healing seen withthe vehicle alone
Antimicrobial Peptides and Skin: A Paradigm of Translational Medicine
Antimicrobial peptides (AMPs) are small, cationic, amphiphilic peptides with broad-spectrum microbicidal activity against both bacteria and fungi. In mammals, AMPs form the first line of host defense against infections and generally play an important role as effector agents of the innate immune system. The AMP era was born more than 6 decades ago when the first cationic cyclic peptide antibiotics, namely polymyxins and tyrothricin, found their way into clinical use. Due to the good clinical experience in the treatment of, for example, infections of mucus membranes as well as the subsequent understanding of mode of action, AMPs are now considered for treatment of inflammatory skin diseases and for improving healing of infected wounds. Based on the preclinical findings, including pathobiochemistry and molecular medicine, targeted therapy strategies are developed and first results indicate that AMPs influence processes of diseased skin. Importantly, in contrast to other antibiotics, AMPs do not seem to propagate the development of antibiotic-resistant micro-organisms. Therefore, AMPs should be tested in clinical trials for their efficacy and tolerability in inflammatory skin diseases and chronic wounds. Apart from possible fields of application, these peptides appear suited as an example of the paradigm of translational medicine for skin diseases which is today seen as a `two-way road' - from bench to bedside and backwards from bedside to bench. Copyright (c) 2012 S. Karger AG, Base
Development and Construction of an Injector Using Hydrogen Cluster Ions for Nuclear Fusion Devices. Status Report as of December 1973
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