Akne.

Akne ist eine chronische Erkrankung mit hoher Prävalenz unter Jugendlichen. Pathogenetische Hauptfaktoren (und ihre klinischen Korrelate) sind gesteigerte Talgproduktion (Seborrhoe), follikuläre Hyperkeratose (Komedonen) und perifollikuläre Entzündungsvorgänge (Papulopusteln). Die Krankheit wird von endogenen (Androgene, IGF-1, neuroendokrine Faktoren) und exogenen (Propionibacterium acnes, Diät, mechanische Irritation, Inhaltsstoffe medizinischer oder kosmetischer Externa) Einflüssen moduliert. Akne geht mit zum Teil hoher Morbidität einher und kann bereits bei leichter Ausprägung eine erhebliche Verschlechterung der Lebensqualität bewirken. Zu Therapie stehen wirksame topische und systemische Behandlungsverfahren zur Verfügung. Eine optimale Behandlung erfordert eine stadiengerechtes Management und kontinuierliche ärztliche Begleitung der Patienten über den erforderlichen Behandlungszeitraum.

Acne.

Acne is a chronic disease with a high prevalence among adolescents. Key pathogenetic factors (and their clinical correlates) are increased sebum production (seborrhea), follicular hyperkeratosis (comedones), and perifollicular inflammation (papules and pustules). The disease is modulated by a variety of endogenous (androgens, IGF-1, neuroendocrine factors) and exogenous (Propionibacterium acnes, diet, friction, ingredients of medical or cosmetic topical products) triggers. Acne is associated with high morbidity, and even mild manifestations may potentially cause considerable impairment in quality of life. Effective topical and systemic treatments are available. Optimal therapeutic results require continuous patient management over the course of the entire treatment period as well as adjustment of treatment modalities based on symptoms and disease severity.

[S2k-guideline for therapy of acne]. / S2k-leitlinie zur therapie der akne.

To optimize the treatment of acne in Germany, the German Society of Dermatology (DDG) and the Association of German Dermatologists (BVDD) initiated a project to develop consensus-based guidelines for the management of acne. The Acne Guidelines focus on induction therapy, maintenance therapy and treatment of post-acne scarring. They include an evaluation of the most commonly used therapeutic options in Germany. In addition, they offer detailed information on how to administer the various treatments and on contraindications, adverse drug reactions, and drug interactions, taking into account gender and special conditions such as pregnancy and lactation. The Acne Guidelines were developed following the recommendations of the Association of Scientific Medical Societies in Germany (AWMF). The treatment recommendations were developed by an expert group and finalized by an interdisciplinary consensus conference. The first choice treatments for acute acne according to acne type are as follows: 1) comedonal acne: topical retinoids; 2) mild papular/pustular acne: fixed or sequential combinations of BPO and topical retinoids or of BPO and topical antibiotics; 3) moderate papular/pustular acne: oral antibiotic plus BPO or plus topical retinoid, or in a fixed combination 4) acne papulo-pustulosa nodosa and acne conglobata: oral antibiotic plus topical retinoid plus BPO or oral isotretinoin. For maintenance treatment: topical retinoid or its combination with BPO. Particular attention should be paid to compliance and quality of life. Additional treatment options are discussed in the main body of the text.

[Antibiotics, azelaic acid and benzoyl peroxide in topical acne therapy]. / Antibiotika, Azelainsäure und Benzoylperoxid in der topische Aknetherapie.

Benzoyl peroxide was introduced as a basic treatment already in acne therapy 1934. The mechanism of action is the reduction of anaerobe bacteria by strong oxidation processes. No resistancies have been ever reported. BPO is available in 2.5, 5 and 10 % formulations. Its efficacy is slightly related to the strength of concentrations, but the side effect profile with burning, erythema and desquamation is increasing with concentrations. BPO 5% mostly is efficient enough to control acne of grades I to II according to the Kligman & Plewig classification. BPO my bleach clothes and hair. It is the most costeffective topical drug in acne of grades I-II. Inflammatory acne of the papular-pustular type I-II can also be treated by topical antibiotics such as erythromycin, clindamycin, and, less frequent and today not anymore recommended tetracyclines. Mechanism of action is not alone an antibacterial but anti inflammatory effect. The efficacy and penetration of the topical antibiotics between the groups are similar. Randomized studies have shown that concentrations of 2-4% are equivalent to oral tetracycline and minocycline in mild to moderate acne. Combinatory formulations with BPO and with retinoids enhance the efficacy significantly. Topical antibiotics plus BPO show less bacterial resistancies as topical antibiotics alone. Antibiotics should therefore not be used as monotherapy. Moreover gram negative folliculitis may develop. Azelaic acid is acting as an antimicrobial and can also reduce comedones. It can also be used in pregnancy and during the lactation period.

[Adjunctive acne therapies--2010]. / Ergänzende Verfahren in der Aknetherapie--Aktualisierung 2010.

Modern acne therapy is based on the application of anticomedogenic, antimicrobial, or antiinflammatory substances, and antiandrogens. Additionally, traditional or newly developed therapeutic approaches may be considered, including pharmacologic (dapsone, zinc) and physical measures (phototherapy, photodynamic therapy, laser, comedone extraction, abrasives). This article reviews such adjunctive therapies with regard to efficacy and their roles in the therapy of acne.

[Adjuvant dermato-cosmetic acne therapy]. / Adjuvante dermatokosmetische Aknetherapie.

Adjuvant dermato-cosmetic therapy in acne is an essential part of the concept of treating acne after initiation and during maintenance therapy. Those are mechanical peeling, chemical peeling and its combination. It needs supervision by an experienced dermatologist.

Phototherapy, photodynamic therapy and lasers in the treatment of acne.

Modern acne therapy uses anticomedogenic, antimicrobial, antiinflammatory,and antiandrogenic substances. As an additional approach in recent years, treatments have been developed based on the application of electromagnetic radiation. Visible light or infrared wave lengths are utilized by most techniques, including blue light lamps, intense pulsed light, photodynamic therapy and lasers. This review evaluates the various methods with regard to efficacy and their current role in the management of acne. Although UV radiation has been frequently used to treat acne, it is now regarded as obsolete due to the unfavorable risk-benefit ratio. Visible light, especially of blue wavelengths, appears to be suitable for the treatment of mild to moderate inflammatory acne. Photodynamic therapy is effective, but, due to considerable immediate side effects, it is best reserved for selected situations. Despite promising observations, intense pulsed light and lasers have to be evaluated in further studies, before they can be recommended.

Pharmacotherapy of acne.

BACKGROUND: Acne results from the interplay of several pathophysiologic factors, in particular seborrhoea, follicular hyperkeratosis, propionibacteria and inflammation. Recently, it has become clear that inflammatory events are important not only in the course, but also in the initiation of the disease. OBJECTIVE: The study undertook an evaluation of the effectiveness of currently available pharmacotherapeutic treatment options for acne. METHODS: After a Medline-based literature search, this article critically reviewed substances used topically (among others, retinoids, antimicrobials, salicylic acid and azelaic acid) and systemically (antibiotics, isotretinoin, hormones and zinc) as well as their combinations with respect to pharmacology, clinical efficacy and side effects. RESULTS: Modern acne pharmacotherapy provides substances that antagonize one or more of the major pathophysiologic factors of acne. When the clinical picture but also patients' motivation and wishes are appropriately considered, current pharmacotherapy of acne is rational and effective.

The efficacy of photodynamic therapy in actinic cheilitis of the lower lip: a prospective study of 15 patients.

BACKGROUND: Photodynamic therapy (PDT) has been developed into a widely used method to treat actinic keratoses and basal cell carcinoma. OBJECTIVE The objective was to assess the efficacy of PDT in the treatment of actinic cheilitis of the lower lip. METHODS: In this prospective, uncontrolled study at a university dermatology department, 15 patients with actinic cheilitis received two sessions of PDT of the lower lip at an interval of 1 week using methylaminoxopentanoate and red light. Clinical and histopathologic evaluation was performed 3 months after therapy. RESULTS: Complete clinical cure was observed in 47% (7/15) and partial cure in another 47% (7/15) of the patients. By histopathologic analysis, residual disease was found in 62% (8/13). Cosmetic results and patients' satisfaction were good to excellent in most cases. Local pain was sufficiently controlled by local anesthesia. CONCLUSION: PDT can be an effective noninvasive method to treat actinic cheilitis of the lower lip.

Effect of subcutaneous infiltration anesthesia on pain in photodynamic therapy: a controlled open pilot trial.

BACKGROUND: Photodynamic therapy (PDT) has been established as a treatment option for nonmelanoma skin cancer, such as superficial basal cell carcinoma, actinic keratoses, or Bowen's disease. OBJECTIVE: A major drawback of PDT is pain during treatment that can cause extreme distress for some patients. METHODS: This study was a controlled, open trial comparing PDT in 16 patients on one side of the face with orally administered analgesics and PDT on the contralateral side of the face with subcutaneous infiltration anesthesia (SIA). The 5-aminolevulinic acid gel was applied 5 hours before treatment. Pain was assessed by the patient using a visual analog scale directly after treatment. RESULTS: Fifteen of 16 (94%) patients reported less pain during PDT after SIA compared to oral analgesics only. This effect was significant (Wilcoxon test for matched pairs, p= .001). No side effects due to SIA were observed. CONCLUSION: SIA is an effective and rather safe method for the control of PDT-associated pain.

[Adjunctive treatments for acne therapy]. / Ergänzende Verfahren in der Aknetherapie.

The mainstays of modern acne therapy include comedolytic, antimicrobial, and anti-inflammatory substances, as well as antiandrogens. Additionally, traditional or newly developed therapeutic approaches may be considered, including pharmacologic (dapsone, zinc) and physical measures (phototherapy, photodynamic therapy, comedone extraction, abrasives). This article reviews such adjunctive therapies with regard to efficacy and their roles in acne therapy.

Elevated 17-hydroxyprogesterone serum values in male patients with acne.

BACKGROUND: Androgen excess may provoke or aggravate acne by inducing seborrhea. In women, androgen disorders are frequently suspected when acne is accompanied by hirsutism or irregularities of the menstrual cycle. In men, however, acne may be the only sign of androgen excess. OBJECTIVE: Our aim was to investigate whether male patients with acne display pathologic androgen blood values. METHODS: This case-control study at a university dermatology department with referred and unreferred patients investigated male acne patients (n = 82, consecutive sample) in whom the diagnosis of mild to severe acne was made, as well as a control group of men without acne (n = 38). The main outcome measures were androgen parameters including morning values of testosterone, luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulfate, androstenedione, and 17-hydroxyprogesterone; as well as a corticotropin stimulation test. RESULTS: 17-Hydroxyprogesterone levels were significantly higher (P = .01) in acne patients than in the control group, whereas the other parameters did not differ significantly. In addition, the corticotropin stimulation test revealed abnormal 17-hydroxyprogesterone induction values in 10 of 82 patients. LIMITATIONS: The analysis is limited to a selection of androgen parameters. CONCLUSION: The results suggest that in men irregularities of adrenal steroid metabolism may be a factor contributing to acne.

Phototherapy and photochemotherapy of sclerosing skin diseases.

The treatment of sclerosing skin diseases [systemic sclerosis, localized scleroderma, lichen sclerosus et atrophicus, sclerodermoid graft-vs.-host disease, scleredema adultorum (Buschke), scleromyxedema and necrobiosis lipoidica] is difficult and remains a great challenge. Numerous treatments, some with potentially hazardous side effects, are currently used with only limited success. The introduction of phototherapy and photochemotherapy for sclerosing skin diseases has considerably enriched the therapeutic panel and proven useful in a number of sclerosing skin diseases especially in localized scleroderma. Two phototherapeutic modalitites are used for the treatment of sclerosing skin diseases, long-wave ultraviolet A and psoralen plus ultraviolet A (PUVA). This article reviews current knowledge about the application of phototherapy and photochemotherapy to various sclerosing skin disorders.

Triplex-forming oligonucleotides - sequence-specific DNA ligands as tools for gene inhibition and for modulation of DNA-associated functions.

The down regulation of gene expression is a promising strategy for molecular medicine and experimental biology. Molecules that bind to the DNA double helix may interfere with gene expression and, in addition to potential therapeutic applications, can be helpful for the investigation of DNA processing, chromatin package, or associated biological processes. Triplex-forming oligonucleotides (TFOs) bind to specific sequences in the DNA double helix via hydrogen bonding interactions. TFOs have been shown to down-regulate gene expression, to induce targeted genomic DNA modifications, to stimulate DNA recombination, and to modulate chromatin organization. Additionally, they may be used as carriers to position DNA-modifying agents to selected sequences. TFO-mediated effects have been mostly described in cell culture, but one study reported TFO activity in a mouse model. Critical issues regarding TFO-based technologies are the development of new oligonucleotide analogues with improved binding affinity, better target selectivity, and sufficient stability in the intracellular environment. A prerequisite for the development of such DNA-binding molecules is the availability of appropriate methods to assess their binding properties quantitatively at the desired target sequence in the genome. This review focuses on recent results regarding gene-inhibitory effects of TFOs in cell culture and methods to evaluate TFO-binding to the desired target sequence in the context of the human genome.

Androgen action on human skin -- from basic research to clinical significance.

Androgens affect several functions of the human skin, such as sebaceous gland growth and differentiation, hair growth, epidermal barrier homeostasis and wound healing. Their effects are mediated by binding to nuclear androgen receptors. Androgen activation and deactivation are mainly intracellular events. They differ from cell type to cell type and between cells at different locations. The major circulating androgens, dehydroepiandrosterone sulfate and androstenedione, are predominantly produced in the adrenal glands, and testosterone and 5alpha-dihydrotestosterone are mainly synthesized in the gonads. Testosterone in women and 5alpha-dihydrotestosterone in both genders are also synthesized in the skin. Skin cells express all androgen metabolizing enzymes required for the independent cutaneous synthesis of androgens and the development of hyperandrogenism-associated conditions and diseases, such as seborrhea, acne, hirsutism and androgenetic alopecia. The major thrust of drug design for the treatment of androgen-associated disorders has been directed against several levels of androgen function and metabolism. Partial effectiveness has only been achieved either by androgen depletion, inhibition of androgen metabolism or blockade of the androgen receptor.

Characterization and quantification of triple helix formation in chromosomal DNA.

DNA-binding molecules that recognize specific sequences offer a high potential for the understanding of chromatin structure and associated biological processes in addition to their therapeutic potential, e.g. as positioning agents for validated anticancer drugs. A prerequisite for the development of DNA-binding molecules is the availability of appropriate methods to assess their binding properties quantitatively at the desired target sequence in the human genome. We have further developed a capture assay to assess triplex-forming oligonucleotide (TFO) binding efficiency quantitatively. This assay is based on bifunctional, psoralen and biotin-conjugated, TFOs and real-time PCR analysis. We have applied this novel quantification method to address two issues that are relevant for DNA-binding molecules. First, we have compared directly the extent of TFO-binding in three experimental settings with increasing similarity to the situation in vivo, i.e. naked genomic DNA, isolated cell nuclei, or whole cells. This comparison allows us to characterize factors that influence genomic triplex formation, e.g. chromosomal DNA organization or intracellular milieu. In isolated nuclei, the binding was threefold lower compared to naked DNA, consistent with a decreased target accessibility int he nucleosomal environment. Binding was detected in whole cells, indicating that the TFO enters the nucleus and binds to its target in intact cells in vivo, but the efficiency was decreased (tenfold) compared to nuclei. Secondly, we applied the method to characterize the binding properties of two different TFOs targeting the same sequence. We found that an antiparallel-binding GT-containing TFO bound more efficiently, but with less target sequence selectivity compared to a parallel-binding CU-containing TFO. Collectively, a sensitive method to characterize genomic triplex formation was described. This may be useful for the determination of factors driving TFO binding efficiency and, thus, may improve the usefulness of triplex-mediated gene targeting for studies of chromatin structure as well as for therapeutic antigene strategies.

Triple helix-mediated inhibition of gene expression is increased by PUVA.

The combination of psoralens with UVA is used as PUVA therapy for psoriasis and other skin diseases. UVA-induced psoralen/DNA photoadducts act via suppression of DNA replication and cell proliferation, but do not sufficiently repress gene transcription. To explore whether PUVA may also be used for gene repression, psoralen was conjugated to a triplex-forming oligonucleotide (TFO) that targets a gene sequence of ICAM-1, a key molecule in cutaneous inflammation. Triplex formation between TFO and target sequence was detected by non-denaturing gel electrophoresis. UVA-irradiation induced psoralen cross-links at the triplex-duplex junction as verified by denaturing gel electrophoresis. When the target sequence was placed within the transcribed portion of the chloramphenicol acetyltransferase (CAT) gene, TFO inhibited CAT expression in A431 cells. Inhibition was sequence-specific, since a scrambled control oligonucleotide or mismatched or scrambled target sequences failed to inhibit CAT expression. Inhibition was not significant without UVA exposure, but was strongly enhanced by PUVA-mediated cross-links at the TFO target site. These results suggest that TFO may add a new quality to PUVA therapy by transcriptionally repressing pathogenically relevant genes, in addition to antiproliferative PUVA effects. TFO designed to repress only after PUVA activation may allow the development of a cutaneous organ specific strategy for gene repression.

Protease inhibitors prevent plasminogen-mediated, but not pemphigus vulgaris-induced, acantholysis in human epidermis.

Pemphigus is an autoimmune blistering disease of the skin and mucous membranes. It is caused by autoantibodies directed against desmosomes, which are the principal adhesion structures between epidermal keratinocytes. Binding of autoantibodies leads to the destruction of desmosomes resulting in the loss of cell-cell adhesion (acantholysis) and epidermal blisters. The plasminogen activator system has been implicated as a proteolytic effector in pemphigus. We have tested inhibitors of the plasminogen activator system with regard to their potential to prevent pemphigus-induced cutaneous pathology. In a human split skin culture system, IgG preparations of sera from pemphigus vulgaris patients caused histopathologic changes (acantholysis) similar to those observed in the original pemphigus disease. All inhibitors that were tested (active site inhibitors directed against uPA, tPA, and/or plasmin; antibodies neutralizing the enzymatic activity of uPA or tPA; substances interfering with the binding of uPA to its specific cell surface receptor uPAR) failed to prevent pemphigus vulgaris IgG-mediated acantholysis. Plasminogen-mediated acantholysis, however, was effectively antagonized by the synthetic active site serine protease inhibitor WX-UK1 or by p-aminomethylbenzoic acid. Our data argue against applying anti-plasminogen activator/anti-plasmin strategies in the management of pemphigus.

Involvement of NF-kappaB signalling in skin physiology and disease.

Transcription factors of the nuclear factor-kappaB (NF-kappaB)/Rel family play a crucial role in gene regulation during a variety of different cellular processes. This review focuses on the increasing knowledge of the role of NF-kappaB in skin physiology and pathology. Several studies demonstrate that NF-kappaB, or components of the system such as IkappaB kinase (IKK)-alpha, seem to be involved in epidermal development and differentiation. Furthermore, a dysregulation of NF-kappaB is suggested to play an important role in skin pathology, including proliferative disorders, e.g. psoriasis, inflammatory processes such as incontinentia pigmenti (IP), sunburn, Lyme disease, allergic contact dermatitis and autoimmune diseases, as well as also in skin carcinogenesis. However, although the knowledge concerning the role of NF-kappaB in the homeostasis of the skin is steadily increasing, many more questions need to be answered.