Improved risk-benefit ratio for topical triamcinolone acetonide in Transfersome in comparison with equipotent cream and ointment: a randomized controlled trial.

BACKGROUND: Transfersome is a drug delivery technology based on highly deformable, ultraflexible lipid vesicles which penetrate the skin when applied non-occlusively. OBJECTIVES: To assess the advantages of this carrier-based formulation in humans, the efficacy and the atrophogenic potential of triamcinolone acetonide (TAC) in Transfersome was compared with commercially available TAC-containing cream and ointment. METHODS: Healthy volunteers were enrolled in double-blind, placebo-controlled clinical trials with random study medication assignment to the test areas. RESULTS: A 10-fold lower dose of TAC in Transfersome(R) (2.5 micro g cm-2) was bioequivalent to 25 micro g cm-2 TAC in conventional formulations as measured by erythema suppression (cream: P = 0.01, ointment: P < 0.001). A skin blanching assay revealed different kinetics of the formulations, with a delayed onset of action of the Transfersome and ointment preparations. Ultrasonic measurements revealed a significantly reduced atrophogenic potential. There was a 12.1% reduction in skin thickness given by TAC in Transfersome compared with a 21.1% reduction given by a bioequivalent dose in TAC cream after a 6-week treatment period (P = 0.007). CONCLUSIONS: Transfersome may significantly improve the risk-benefit ratio of topically applied glucocorticosteroids.

Invasion of human keratinocytes by Staphylococcus aureus and intracellular bacterial persistence represent haemolysin-independent virulence mechanisms that are followed by features of necrotic and apoptotic keratinocyte cell death.

BACKGROUND: Colonization of human skin by Staphylococcus aureus is a characteristic feature of several inflammatory skin diseases, which is often followed by tissue invasion and severe cell damage. A crucial role has been attributed to staphylococcal haemolysins in the cytotoxicity to epidermal structures. OBJECTIVES: To investigate haemolysin-independent virulence to human keratinocytes. METHODS: The stable alpha-haemolysin, beta-haemolysin double-negative S. aureus mutant DU 5720 was compared with the fully virulent parent strain 8325-4 and with its isogenic fibronectin-binding protein A/B-negative variant DU 5883 in an invasion model. RESULTS: This assay showed dose-dependent internalization of all the strains investigated by human HaCaT keratinocytes, with reduced internalization of DU 5883. Transmission electron microscopy revealed adhesion of staphylococci to cellular pilus-like extrusions, followed by the embedding of the bacteria in cellular grooves. Following attachment to the keratinocytes the staphylococci were engulfed into vesicles within the cytoplasm where some bacteria persisted for 24-48 h. Addition of cytochalasin D strongly reduced the bacterial uptake, suggesting an active keratinocyte process. Bacterial invasion was followed by severe keratinocyte cell damage showing the morphological changes of cytotoxic and, to a lesser extent, apoptotic cell death as determined by the trypan blue exclusion test and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling assay. The highest levels of lethal cytotoxicity were observed in haemolysin-producing strains, whereas the induction of apoptosis seemed to depend on internalization. CONCLUSIONS: Staphylococcal invasion of human keratinocytes represents a potent staphylococcal virulence factor, which, independently of alpha- and beta-haemolysins, leads to necrotic and apoptotic cell damage.

Dihydroxyacetone in a new formulation--a powerful therapeutic option in vitiligo.

BACKGROUND: Most treatment protocols for vitiligo require a long treatment duration and usually do not result in complete repigmentation. Therefore, cosmetically acceptable and easily to handle alternatives are warranted. OBJECTIVE: To evaluate the properties of dihydroxyacetone (DHA) in a new formulation for the treatment of vitiligo on exposed areas. METHODS: We treated 10 patients suffering from vitiligo affecting the face and/or hands with a newly introduced, commercially available self-bronzing cream containing DHA 5%. DHA was applied every second day. RESULTS: The characteristic pigmentation showed very satisfactory cosmetic results in 8 out of 10 patients after 2 weeks of treatment. CONCLUSION: The new DHA formulation is a practical and well-accepted treatment modality.

Defense against influenza A virus infection: essential role of the chemokine system.

Monocytes/macrophages are highly susceptible to an infection with influenza A virus. After infection, de novo virus protein synthesis is detectable but rapidly interrupted before completion of the first viral replication cycle. Within 24-48 hours the infected monocytes die by apoptosis. Before cell death, infected monocytes initiate a cell-specific immune response. This includes the transcription and subsequent release of TNF-alpha (tumor necrosis factor alpha), IL-1beta (Interleukin 1beta), IL-6, type I inferferons and CC chemokines. Enhanced cytokine mRNA expression is due to a prolonged mRNA stability and an augmented gene transcription. Activation of transcription factors such as NF-kappaB (nuclear factor kappaB) and AP-1 are involved in activation of cytokine mRNA transcription. Infection of monocytes with influenza A virus induces the selective expression of mononuclear leukocyte attracting chemokines, such as MCP-1 (monocyte chemotactic protein 1), MIP-1alpha (macrophage inflammatory protein 1alpha) and RANTES (regulated upon activation, normal T cell expressed and secreted). In striking contrast, the release of the neutrophil-specific chemokines IL-8 (interleukin 8) and GRO-alpha (growth stimulatory activity alpha) is entirely suppressed. This differentially regulated chemokine expression may explain the mononuclear cell infiltrate characteristic for virus-infected tissue. Thus, infection of monocytes/macrophages with influenza A virus primes for a rapid proinflammatory reaction and induces an enhanced immigration of mononuclear cells into infected tissue. Taken together, these mechanisms may prepare the infected host for a fast and virus-specific immune response.

Optimizing the therapeutic approach in tinea capitis of childhood with itraconazole.

BACKGROUND: Tinea capitis is the most common dermatophytosis of childhood with increasing incidence. Whereas griseofulvin is considered by many as the mainstay of treatment, newer oral antifungal agents, including fluconazole, itraconazole and terbinafine have demonstrated higher efficacy, resulting in shorter treatment durations. OBJECTIVES: We aimed to determine the optimum regimen for the treatment of childhood tinea capitis with itraconazole. METHODS: A mycological culture outcome-dependent combination of a 28-day continuous and facultative additional 14-day courses with itraconazole was used in 42 children (20 girls; 22 boys) aged 12-140 months (mean 66) with tinea capitis due to Microsporum canis (n = 26) and Trichophyton violaceum (n = 16). The drug was given orally according to the patients' body weight (50 mg daily for < 20 kg; 100 mg daily for > or = 20 kg) over 4 weeks. Direct microscopy and fungal culture as a parameter for efficacy were repeated 2 weeks after termination of treatment. Assessment of efficacy was based on the evaluation of results from light microscopy and culture at 8 weeks after initiation of treatment, and in the case of a further positive mycological culture at 14 and 20 weeks, respectively. A positive fungal culture at these times resulted in an additional course for 2 weeks with the initially chosen itraconazole dosage. RESULTS: In 34 of 42 patients a single 4-week course of itraconazole resulted in a complete mycological cure of lesions as demonstrated by light microscopy and mycological culture. Four of 42 patients had to be treated by a second itraconazole course for 2 weeks, and four children received a third course of itraconazole for 2 weeks until all lesions showed negative direct microscopy and mycological culture. No abnormal haematological or biochemical results occurred. Apart from transient, completely reversible indigestion in two children, no side-effects were observed. CONCLUSIONS: A culture-based 28-day continuous therapeutic regimen plus facultative cultural outcome-dependent additional 14-day courses of a body weight-adapted dosage of itraconazole in tinea capitis due to M. canis and T. violaceum is discussed; this offers the advantage of an effective therapy with complete negative direct microscopy as well as negative cultural results, within a shorter active treatment period (cf. previous studies with continuous administration of itraconazole).

Systemic vitamin C and vitamin E do not prevent photoprovocation test reactions in polymorphous light eruption.

The possible influence of oxidative stress is discussed in the pathogenesis of polymorphous light eruption (PLE). A double-blind, placebo-controlled study of prophylactic treatment with systemic administration of vitamin C (3 g/d) and E (1500 IU/d) for 8 days was undertaken in 9 patients with PLE (verum, n=4; placebo, n=5). Evaluation of the maximal effects after photoprovocation before and after intake of the antioxidants revealed a reduction of most skin reactions (overall skin reaction, papules/vesicles) in both groups with marked differences in the placebo group. The antioxidants in the doses given and over the time period used did not influence the development of PLE, but might interfere with immunosuppressive effects of repeated photoprovocation tests.

Changes in collagen I and collagen III metabolism in patients with generalized atopic eczema undergoing medium-dose ultraviolet A1 phototherapy.

Fourteen patients suffering from acute, exacerbated atopic eczema were screened for changes in collagen I and collagen III metabolism in serum (n = 11), urine (n = 11) and skin biopsies (n = 9) before and after medium-dose ultraviolet (UV) A1 phototherapy (15 exposures of 50 J/cm2 over a 3-week period, total dose 750 J/cm2). Mature collagen I and, to a lesser extent, mature collagen III were found to be decreased after the therapy in skin samples from the irradiated patients. As markers of collagen I degradation, the cross-links pyridoline and deoxypyridoline were analysed in urine using high-performance liquid chromatography. Both cross-links were found to be mildly increased after UVA1 phototherapy, without reaching statistical significance. As markers of de novo collagen synthesis we screened for the procollagen I-carboxyterminal peptide (PICP) and procollagen III-aminoterminal peptide (PIIINP) levels in serum and skin. The ratio of PICP to PIIINP in serum dropped significantly after the UVA1 phototherapy, suggesting a different impact of UVA1 on the two collagens. These findings were paralleled by a diminished ratio of PICP to PIIINP in tissue samples. Staining for matrix metalloproteinase 1 (MMP-1) and its specific counterpart, tissue inhibitor of MMP-1 (TIMP-1), showed slight increases for both proteins by therapeutic UVA1; this was also seen in serum for TIMP-1 but not MMP-1. In our study, high-energy UVA1 doses induced changes of the skin collagens in patients with atopic eczema which are measurable by their metabolites in serum and urine.

Long-term efficacy of medium-dose UVA1 phototherapy in atopic dermatitis.

BACKGROUND: UVA1 (340-400 nm) therapy proved to be highly effective in patients with severe atopic dermatitis. The optimal dose regarding therapeutic efficacy and possible side effects is still to be evaluated. In vitro cell culture as well as in vivo animal studies recently indicated that a correlation between UVA irradiation and photoaging, skin carcinogenesis, or melanoma induction may exist. Therefore it seems appropriate to focus research activities on reducing the UVA1 dose applied during phototherapeutic regimens minimizing nonbeneficial side effects. OBJECTIVE: The present study was performed to evaluate the therapeutic effectiveness and long-term efficacy of medium-dose UVA1 irradiation in patients treated for acute exacerbated atopic dermatitis. METHODS: Thirty-two patients underwent a medium-dose UVA1 therapy consisting of 15 treatments applied from Monday to Friday for a period of 3 weeks. The applied dose per treatment was 50 J/cm(2) resulting in a cumulative dose of 750 J/cm(2). Clinical severity was assessed according to the SCORAD index before and after irradiation as well as in monthly intervals up to 3 months after cessation of phototherapy. RESULTS: Medium-dose UVA1 phototherapy is effective for alleviating acute exacerbated atopic dermatitis as shown by a significant reduction of SCORAD ratings (P <.001) at the end of the active UV treatment period. A significant skin improvement was still present 1 month later (P <.001). However, at the end of the 3-month posttreatment observation period the skin condition had reached the pretreatment level. CONCLUSION: According to our data, medium-dose UVA1 phototherapy is a highly effective, nonsteroidal, therapeutic alternative for treatment of acute exacerbated atopic dermatitis. However, effectiveness is merely short term, limited, and is followed by recurrence of symptoms within a 3-month observation interval.

[Treatment of acute exacerbated atopic eczema with emollient-antiseptic preparations using the "wet wrap" ("wet pajama") technique]. / Behandlung des akut exazerbierten atopischen Ekzems mit fett-feuchten Verbänden und topischem Chlorhexidin.

Six patients (3 children and 3 adults) with acute exacerbated atopic eczema were treated with basic emollients in combination with chlorhexidine-soaked dressings over a period of three days using the "wet-pyjama" technique. Improvement of eczema was documented with the severity score "Scoring of Atopic Dermatitis" (SCORAD); most pronounced changes were found for the subjective parameters itch and sleep loss. Paralleling skin improvement a reduction of Staphylococcus aureus colonisation was noted. Improvement of skin changes lasted beyond the active treatment period. Wet-wrap dressings are an effective treatment modality for atopic eczema without use of corticosteroids and can be used easily on an outpatient basis when manufactured dressings are used.

Programmed cell death (apoptosis) in human monocytes infected by influenza A virus.

Although infection of monocytes by influenza A virus primes for a high cytokine release, it also leads to cell death within 20-30 hours. In this brief report, we demonstrate that influenza A virus-induced monocyte killing was due to programmed cell death (apoptosis) and not to necrosis. Morphologically, chromatin condensation and margination occurred and biochemically, an apoptosis-specific internucleosomal DNA fragmentation into multimers of 180 bp ("DNA ladder") was found. Induction of apoptosis and not necrosis in influenza A virus-infected monocytes may serve three purposes: 1. Virus replication is limited, 2. a priming for a high cytokine response is initiated and 3. damaging and inflammation-inducing lysosomal enzymes are held back from monocytes undergoing controlled cell death.