397 research outputs found
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
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
The pH of the skin surface and its impact on the barrier function
The `acid mantle' of the stratum corneum seems to be important for both permeability barrier formation and cutaneous antimicrobial defense. However, the origin of the acidic pH, measurable on the skin surface, remains conjectural. Passive and active influencing factors have been proposed, e. g. eccrine and sebaceous secretions as well as proton pumps. In recent years, numerous investigations have been published focusing on the changes in the pH of the deeper layers of the stratum corneum, as well as on the influence of physiological and pathological factors. The pH of the skin follows a sharp gradient across the stratum corneum, which is suspected to be important in controlling enzymatic activities and skin renewal. The skin pH is affected by a great number of endogenous factors, e. g. skin moisture, sweat, sebum, anatomic site, genetic predisposition and age. In addition, exogenous factors like detergents, application of cosmetic products, occlusive dressings as well as topical antibiotics may influence the skin pH. Changes in the pH are reported to play a role in the pathogenesis of skin diseases like irritant contact dermatitis, atopic dermatitis, ichthyosis, acne vulgaris and Candida albicans infections. Therefore, the use of skin cleansing agents, especially synthetic detergents with a pH of about 5.5, may be of relevance in the prevention and treatment of those skin diseases. Copyright (c) 2006 S. Karger AG, Base
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
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
Impact of Age and Body Site on Adult Female Skin Surface pH
Background: pH is known as an important parameter in epidermal barrier function and homeostasis. Aim: The impact of age and body site on skin surface pH (pH(SS)) of women was evaluated in vivo. Methods: Time domain dual lifetime referencing with luminescent sensor foils was used for pH(SS) measurements. pH(SS) was measured on the forehead, the temple, and the volar forearm of adult females (n = 97, 52.87 +/- 18.58 years, 20-97 years). Every single measurement contained 2,500 pH values due to the luminescence imaging technique used. Results: pH(SS) slightly increases with age on all three investigated body sites. There are no significant differences in pH(SS) between the three investigated body sites. Conclusion: Adult pH(SS) on the forehead, the temple and the volar forearm increases slightly with age. This knowledge is crucial for adapting medical skin care products. Copyright (C) 2012 S. Karger AG, Base
Multi-drugs resistant acne rosacea in a child affected by Ataxia-Telangiectasia: successful treatment with Isotretinoin
State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology.
Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain--are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing
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