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  • 1
    ISSN: 1573-904X
    Keywords: topical glucocorticoids ; keratinocytes ; fibroblasts ; interleukins ; benefit-risk ratio
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacodynamic characterization of topical glucocorticoids as prednicarbate (PC), its metabolites prednisolone 17-ethylcarbonate (PEC) and prednisolone (PD), betamethasone 17-valerate (BMV), beta-methasone (BM) and desoximetasone (DM) by evaluating their effects on epidermal and dermal cells. Synopsis of pharmacokinetic and pharmacodynamic studies, possibly explaining the improved benefit-risk ratio of prednicarbate. Methods. Isolated foreskin keratinocytes were used to investigate the influence on epidermal inflammatory processes, dermal fibroblasts of the same origin to study antiproliferative activities of glucocorticoids. Interleukins were measured by ELISA-assay, the influence on II-lα-production also on mRNA-level by RNAse protection assay. Proliferation was assessed by 3H thymidine incorporation and biodegradation by HPLC/UV-absorption. Cell viability was controlled by MTT assay. Results. In keratinocytes, inflammation was induced by TNFα, resulting in an increased II- lα synthesis. This cytokine was particularly suppressed by PC and BMV, whereas PEC, PD, DM and BM were less potent (p ≤ 0.05). Since, however, the double ester PC is rapidly degraded in keratinocytes, a RNAse-protection assay of II-1α mRNA was performed allowing short incubation times and thus minimizing biodegradation effects. In agreement with the previous experiment, the antiinflammatory potency of native PC was confirmed. In fibroblasts, II-lα and II-6 synthesis indicate proliferation and inflammation respectively. Whereas PC inhibited II- lα and II-6 production in fibroblasts to a minor extent only, it was strongly reduced by the conventional glucocorticoids and PEC (p ≤ 0.05). The minor unwanted effect of PC on fibroblasts was also reflected by its low influence on cell proliferation as assayed by 3H thymindine incorporation. More pronounced antiproliferative features were observed with BM, PEC and espectially BMV. Conclusions. Correlating antiphlogistic effects in keratinocytes (suppression of II-lα) with antiproliferative effects in fibroblasts (suppression of II-lα and II-6), the improved benefit−risk ratio of PC compared to conventional glucocorticoids does not result only from distinct drug metabolism in the skin but also from a specific influence on the cytokine network.
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  • 2
    ISSN: 1573-904X
    Keywords: prednicarbate ; topical glucocorticoids ; pharmacokinetics ; biotransformation ; keratinocytes ; fibroblasts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Evaluation of skin layer-specific prednicarbate (PC) biotransformation, possibly explaining the improved benefit/risk ratio of this topical corticosteroid in atopic dermatitis (1,2). Methods. Metabolism of PC in keratinocyte and fibroblast monolayers derived from human juvenile foreskin was evaluated. Drug concentration was determined by HPLC/UV-absorption. Accompanying cell viability tests (MTT-tests) were performed to exclude toxic drug effects. Results. Keratinocytes hydrolyzed the double ester PC (2.5 × 10−6 M) at position 21 to the monoester prednisolone 17-ethylcarbonate (P17EC) which nonenzymatically transformed to prednisolone 21-ethylcarbonate (P21EC). This metabolite was enzymatically cleaved to prednisolone (PD), the main biotransformation product at 24 hours. Fibroblasts, however, showed a distinctively lower enzyme activity. Both, PC and P17EC (or rather P21EC) were hydrolyzed to a minor extent only. The biotransformation pathway, however, was the same. When P17EC was added separately, it transformed to P21EC and again was cleaved by keratinocytes to a much higher extent. Despite of the rather high glucocorticoid concentration MTT-tests proved a non-disturbed cell viability and proliferation rate. Conclusions. Extrapolating our results to the in-vivo situation, topically applied PC may be metabolized by epidermal cells during skin penetration. A complex mixture of compounds reaches the dermis, whose fibroblasts are barely able to metabolize the steroids. Since skin atrophy is less pronounced with PC as compared to conventional halogenated glucocorticoids, less potent PC metabolites appear to be the dominant species in the dermis.
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  • 3
    ISSN: 1573-904X
    Keywords: benefit/risk ratio ; drug metabolism ; prednicarbate ; skin penetration ; topical glucocorticoids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To investigate pharmacokinetic differences between the non-halogenated double ester prednicarbate (PC) and the fluorinated monoester betamethasone 17-valerate (BM17V) their metabolism in human keratinocytes and fibroblasts as well as their permeation and biotransformation in reconstructed epidermis and excised human skin was compared. Special attention was given to the 17-monoesters because of their high receptor affinity and antiproliferative effects. Methods. Glucocorticoid penetration was determined using Franz diffusion cells, quantifying metabolite concentrations by HPLC. Chemical stability and reactivity of the monoesters was determined by molecular modeling analysis. Results. PC accumulated in the stratum corneum. A considerable amount of penetrating PC was hydrolyzed by viable keratinocytes to prednisolone 17-ethylcarbonate (P17EC). P17EC permeated the skin very rapidly when compared to BM17V. Overall P17EC concentrations in viable tissue were low. Inside of the acceptor fluid, but not within the tissue, P17EC was converted to the more stable prednisolone 21-ethylcarbonate (P21EC). Conclusions. The inactivation of highly potent, but also cell toxic, 17-monoesters to almost inactive 21-congeners seen with isolated cell monolayers appears less important in the skin. In vitro determination of the dermal 17-monoesters concentrations may allow the prediction of the atrophogenic risk in man. BM17V levels exceeding P17EC concentrations about 6-fold may contribute to its lower tolerance when compared to PC.
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  • 4
    ISSN: 1432-1173
    Keywords: Schlüsselwörter Mycobacterium avium-intracellulare ; Dermatomyositis ; Immunsuppressiva ; Atypische Mykobakteriose ; Key words Mycobacterium avium-intracellulare ; Dermatomyositis ; Immunosuppressive therapy ; Atypical mycobacteriosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary The ubiquitous Mycobacterium avium-intracellulare (MAI) is the most frequent cause of disseminated atypical mycobacteriosis in AIDS patients. MAI infections may develop in patients with other acquired immune defects, such as connective tissue disorders. In adults, the gastrointestinal and respiratory systems are most frequently affected. We report a patient with dermatomyositis receiving immunosuppressive therapy in whom only the skin and the skeletal system were affected by MAI. Because it presented with polymyositis-like symptoms, the infection was initially not identified and treated. The MAI was cultured from a periarticular joint effusion from the right upper arm and from venous blood, as well as identified histologically in lesional skin. Resistance to antibiotics developed most likely because the patient failed to take oral antibiotics regularly. Because of an acute exacerbation of the tumor-associated dermatomyositis, immunosuppressive therapy was initiated, while the tuberculostatic therapy was continued. Using these therapies both diseases markedly improved. In patients with connective tissue disorders receiving longterm immunosuppressive therapy, especially when changes in symptoms and signs are observed, opportunistic infections such as MAI should be considered and included in the differential diagnosis.
    Notes: Zusammenfassung Als häufigster Erreger einer disseminierten atypischen Mykobakteriose wird heute bei AIDS-Patienten das ubiquitär vorkommende Mycobacterium avium-intracellulare gefunden. Aber auch im Verlauf eines anderen erworbenen Immundefektes, etwa im Rahmen von Kollagenosen, kann Mycobacterium avium-intracellulare als Erreger auftreten. Beim Erwachsenen sind dabei überwiegend der Gastrointestinal- und Respirationstrakt betroffen. Wir berichten über eine unter immunsuppressiver Therapie stehende Patientin mit Dermatomyositis, bei der ein isolierter Befall der Haut und des Skelettsystems mit atypischen Mykobakterien bestand. Aufgrund der anfangs Polymyositis-artigen Beschwerden der Mykobakteriose wurde die Infektion zunächst nicht erkannt und nicht behandelt. Der Erregernachweis gelang kulturell aus dem Punktat eines periartikulären Ergusses am rechten Oberarm, aus Venenblut, sowie mikroskopisch in Biopsien aus befallener Haut. Eine Resistenzverschiebung war infolge unregelmäßiger Antibiotikaeinnahme festzustellen. Wegen eines akuten Schubes der tumorassoziierten Dermatomyositis wurde, unter Weiterführung der tuberkulostatischen Therapie, eine immunsuppressive Behandlung eingeleitet: darunter kam es zu einer deutlichen Besserung beider Krankheitsbilder. Bei Kollagenosepatienten unter langjähriger immunsuppressiver Therapie sollte insbesondere bei einem Wandel der Beschwerden auch an opportunistische Infektionen wie zum Beispiel an eine atypische Mykobakteriose gedacht werden.
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  • 5
    Electronic Resource
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    Springer
    Der Hautarzt 49 (1998), S. 243-252 
    ISSN: 1432-1173
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Lernziel Der vorliegende Fortbildungsartikel faßt die wesentlichen klinischen, ätiopathogenetischen und aktuellen therapeutischen Aspekte der Pyodermien zusammen und ermöglicht nach seiner Durcharbeitung die sichere Einordnung und Behandlung der besprochenen Erkrankung.
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  • 6
    ISSN: 1432-1173
    Keywords: Schlüsselwörter: Andrologie – Spermatozoen – Immotile-Zilien-Syndrom – Zentraltubuli – 9+0-Tubulusmuster ; Key words: Andrology – Spermatozoa – Immotile cilia syndrome – Central tubules – 9+0 tubular pattern
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract. A man presented with 100% immotile spermatozoa. Transmission electron microscopy showed the absence of both central tubules in all sperm tails; the nine peripheral tubules, dynein arms, radial spokes and other structures of the sperm tail were normal. Immotile cilia syndrome of the 9+0 tubular pattern was diagnosed. Other anomalies frequently associated with immotile cilia syndrome, such as recurrent airway infections, bronchiectases and situs inversus (Kartagener's syndrome), were not present in this case.
    Notes: Zusammenfassung. Ein Patient der andrologischen Sprechstunde wies ausschließlich unbewegliche Spermatozoen auf. Die Transmissionselektronenmikroskopie zeigte ein Fehlen der beiden Zentraltubuli in allen Spermatozoenschwanzstücken; die neun peripheren Doppeltubuli, Dyneinarme, Radialspeichen und andere Strukturen des Flagellums waren normal angelegt. Es wurde ein Immotile-Zilien-Syndrom vom sogenannten 9+0-Tubulusmuster diagnostiziert. Mit Immotile-Zilien-Syndromen häufig assoziierte Anomalien wie rezidivierende Atemwegsinfekte, Bronchiektasen oder Situs inversus (Kartagener-Syndrom) lagen bei dem Patienten nicht vor.
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  • 7
    ISSN: 1432-1173
    Keywords: Schlüsselwörter Seborrhoisches Ekzem ; Dithranoltherapie ; Dithranoldermatitis ; Magistralrezeptur ; Key words Seborrhoic dermatitis ; Dithranol treatment ; Dithranol dermatitis ; Compounding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Seborrhoic dermatitis is an erythemato-squamous condition of unknown etiology with a prevalence of approximately 2.5%. Frequently difficult to treat, it may respond to the application of low doses of dithranol, a substance which can induce a pustular dermatitis as an adverse side effect depending on the applied concentration and individual susceptibility. We describe a pustular dermatitis after the application of a preparation containing dithranol at an erroneously high concentration in a 30-year-old patient with seborrhoic dermatitis.
    Notes: Zusammenfassung Das seborrhoische Ekzem ist eine pathogenetisch ungeklärte erythematosquamöse Hauterkrankung mit einer Prävalenz von etwa 2,5%. Die häufig schwierig zu behandelnden Hautveränderungen sprechen gelegentlich gut auf die topische Applikation niedriger Dosen von Dithranol an, einer Substanz, die jedoch als unerwünschte Wirkung abhängig von verwendeter Konzentration und individueller Empfindlichkeit eine pustulöse Dermatitis auslösen kann. Wir berichten über das Auftreten einer pustulösen Dermatitis nach Anwendung eines fälschlich 50fach zu hoch konzentrierten Dithranolpräparates der magistralen Rezeptur bei einem 30jährigen Patienten mit seborrhoischem Ekzem.
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  • 8
    ISSN: 1432-2307
    Keywords: Malignant melanomas ; Cryostat sections ; Major diagnostic criteria ; Variance analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Although cryostat sections in general allow a distinction to be made between malignant melanomas and other pigmented lesions in clinically doubtful cases, the differential diagnosis may be difficult. The histological and cytological criteria taken into account can be classified as major, minor, and insufficient. Knowing the diagnostic value of each makes a conventionally established diagnosis safer. Variance analysis does not contribute to the problem but it can nevertheless be shown that the evaluation of six major criteria makes a quick and reliable cryostat section diagnosis possible. If these results are confirmed in a prospective study it would be a decisive step on the way to a quicker and safer cryostat section diagnosis of malignant melanoma, even for the less experienced histopathologist.
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  • 9
    ISSN: 1432-1440
    Keywords: Key words Candida albicans ; Candida sake ; Human immunodeficiency virus infection ; Oral candidosis ; Polymerase chain reaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Candida sake is routinely identified in the oral cavity of patients infected with the human immunodeficiency virus (HIV) using the commercial identification system ATB 32 C. To establish the prevalence of C. sake and to evaluate this designation repeatedly found using the ATB 32 C system, 94 HIV-infected patients were investigated for the presence of oral candidosis based on clinical and microbiological grounds. A total of 186 Candida isolates from 62 patients were obtained. Using the assimilation assay, C. sake was suspected in 49 isolates, but only seven strains were positively identified according to ATB 32 C. With respect to antifungal susceptibility and clinical parameters the 49 strains did not differ markedly from the other strains. Only antifungal susceptibility to amphotericin B, ketoconazole, and flucytosine was increased in C. sake strains when the positively and equivocally identified strains by ATB 32 C were taken together. In addition, amplifying genomic DNA with primers T3B and AP3, C. sake could not be identified in four strains and in one strain, respectively. Therefore biochemical identification of C. sake seems to be misleading and clinical relevance may be lacking.
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  • 10
    ISSN: 1365-2958
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: Candida glabrata has emerged as one of the most common causes of candidosis. In order to identify factors that are necessary for viability and pathogenicity of this fungal pathogen, we analysed the role of the KEX2 gene, which codes for a regulatory endoproteinase that is known to process certain virulence factors in Candida albicans. The KEX2 gene from C. glabrata was cloned and found to have 51% and 62% identity and high structural similarities to the homologous counterparts in C. albicans and Saccharomyces cerevisiae. KEX2 was expressed at all time points investigated during growth in complex medium. In order to investigate the role of this putative regulatory proteinase, Kex2-deficient mutants were produced. In addition to known kex2 phenotypes, such as pH and calcium hypersensitivity, the mutants grew in cellular aggregates and were found to be hypersensitive to several antifungal drugs that target the cell membrane, including azoles, amorolfine and amphotericin B. Ultrastructural investigation after exposure to low doses of itraconazole showed azole-specific alterations such as enlarged vacuoles and proliferation of the cytoplasmatic membrane in the kex2 mutants, but not in the control strains. In contrast, antifungals such as 5-flucytosine and hydroxypyridones inhibited growth of the kex2 mutants and the control strains to the same extent. In an in vitro model of oral candidosis, kex2 mutants showed reduced tissue damage in the presence of itraconazole compared with the control infections. These data suggest that Kex2 is involved in the processing of proteins that are essential for cell surface integrity of C. glabrata.
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