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M Schäfer-Korting

Publications and source records attributed to M Schäfer-Korting.

At least 37 records · Page 2Linked to original sources
PubMed1999

Fusion of the binding domain of Raf-1 kinase with green fluorescent protein for activated Ras detection by fluorescence correlation spectroscopy.

Ras proto-oncogenes play a central role in cell proliferation by the regulation of signal transduction pathways from receptors of the outer cell membrane to the nucleus via the activation of transcription factors. Wild-type Ras cycles between the activated GTP-bound and the inactivated GDP-bound state, and the GTPase reaction is a timer for the interaction between Ras-GTP and effector molecules such as Raf-1 protein kinase. Mutations of ras resulting in the loss of the intrinsic GTPase activity result in autonomous proliferation. Mutated Ras is found in a variety of human tumors. Therefore, monitoring of GTP-loaded conformation of Ras related proteins could be utilised in cancer diagnosis. To develop a fluorescence based bioassay we have coupled the gene for the N-terminal Ras binding domain (RBD) of Raf-1 protein kinase with the gene for the green fluorescent protein (GFP). The chimeric fusion protein RBDGFP was identified by immunoblotting and subsequently investigated by fluorescence correlation spectroscopy (FCS), a new analytical technology allowing the measurement of characteristic diffusion times of fluorescently labeled molecules. Molecular interactions increase the molecular weight and influence the diffusion time of RBDGFP. FCS diffusion value of the recombinant protein was in coincidence with the molecular weight of the construct. Fluorimetric measurements of RBDGFP versus GFP showed clearly that the recombinant protein contains functional GFP. Increased FCS transition times indicated the interaction of RBDGFP with its corresponding antibody. Suboptimal binding of the fusion protein to activated Ras, how ever, resulted in a modest influence on the diffusion value. Taken together our rational design and construct shows the way for a ready characterisation of novel GFP-connected fusion proteins employing FCS.

Blotting, Western↗
PubMed1999

[Tridimensional skin models recording percutaneous absorption]

Today there is a lack of generally accepted alternatives to animal experiments for the evaluation of percutaneous absorption or skin penetration. To evaluate the potential of commercially available reconstructed epidermis we compared the barrier function of the three dimensional human skin equivalents Episkintrade mark, EpiDermtrade mark, and Skinethictrade mark to those of excised human skin. Moreover the batch-to-batch variation of skin equivalents was determined. Methods for evaluation included the determination of transepidermal water loss (TEWL) and of the prednisolone (PD) penetration. Whereas TEWL values of Skinethictrade mark and EpiDermtrade mark were very close (15 g·m-2·h-1), PD-penetration showed a clearly superior barrier function with the Skinethictrade mark model. Drug penetration was only 50% of the EpiDermtrade mark model and PD concentrations in the acceptor medium amounted to 150 ng/ml as compared to 300 ng/ml. The highest values were obtained with the Episkintrade mark model (20 g·m-2·h-1, 500 ng/ml). Therefore this model has the poorest barrier function. The TEWL value for human skin was 9 g·m-2·h-1 and PD concentrations in the acceptor medium were below the limit of detection (10.1 ng/ml). Because of the superior barrier function of the Skinethictrade mark the following evaluation was only performed using this model. Batch-to-batch variation was less than with human skin (interindividual variation of 2 h TEWL 12% and > 19%). Despite of the slightly less well-developed barrier, this skin model clearly appears superior with respect to the reproducibility of data. Therefore future investigations on the potential of human skin equivalents for the determination of percutaneous absorption appear very promising.

Journal Article↗
PubMed1998

De novo expression of the alpha5beta1-fibronectin receptor in HT29 colon-cancer cells reduces activity of C-SRC. Increase of C-SRC activity by attachment on fibronectin.

Changes in integrin expression during malignant transformation have been observed in many tumors. Colon-carcinoma cells show reduced expression or even loss of the alpha5beta1 integrin compared to normal or adenoma cells. To determine the significance of absent alpha5beta1 integrin signaling, we transfected the cDNA coding for the alpha5 integrin sub-unit into the human colon-carcinoma cell line HT29, which constitutively lacks this subunit but does express the beta1 subunit. We show here that the newly expressed fibronectin receptor alpha5beta1 generates multiple signals, causing marked changes in cytoskeletal arrangements within a few minutes of adhesion to fibronectin. Cells expressing the alpha5beta1 integrin exhibit the formation of actin stress fibers and focal adhesions, as well as the induction of tyrosine phosphorylation of several proteins, within 10 min. We identified the focal adhesion kinase pp125FAK and the cytoskeletal protein paxillin as major phosphorylation substrates in these cells. These proteins remained hypophosphorylated when alpha5-negative control cells were plated on fibronectin. The tyrosine kinase pp60c-src, regarded as central in the regulation of cellular proliferation and constitutively over-expressed in HT29 and in colon-carcinoma cells, showed reduced intrinsic kinase activity in unstimulated HT29alpha5 cells. In contrast, fibronectin-induced signaling through alpha5beta1 increased pp60c-src activity. Moreover, immunoprecipitation of pp60c-src from extracts of HT29alpha5 cells cultivated on fibronectin for 20 min revealed complex formation of pp60c-src and tyrosine-phosphorylated pp125FAK. Our data suggest that de novo expression of the alpha5beta1 integrin in HT29 colon-cancer cells restores signaling via pp125FAK and pp60c-src. Thus, loss of this receptor during malignant transformation may contribute to tumor-cell autonomy, while reduced activity of pp60c-src in HT29alpha5-cells may participate directly in growth control.

Cell Adhesion↗
PubMed1998

Effects of growth factors on the proliferation of human keratinocytes and fibroblasts in vitro.

Growth/differentiation factor-5 (GDF-5) is a new member of the transforming growth factor-beta (TGF-beta) superfamily of multifunctional peptide growth factors that appear to mediate many key events in cell growth and development. The effects of GDF-5 and other growth factors (epidermal growth factor, EGF; TGF-beta 1) on the proliferation of human keratinocytes and fibroblasts compared with desoximetasone and calcipotriol have been investigated. The proliferation rate was determined by a hemocytometer, MTT assay and the incorporation of [3H]-thymidine. Moreover, cell cycle analyses were performed and the influence on interleukin-1 alpha (IL-1 alpha) production in keratinocytes was measured by enzyme-linked immunosorbent assay (ELISA) because of its pronounced proinflammatory effect. In keratinocytes, GDF-5 stimulated cell proliferation to a minor extent. The drug already proved to be effective at very low concentrations (0.1 ng/ml). Growth stimulatory effects with EGF have been observed only in keratinocyte basal medium (KBM), but not in keratinocyte growth medium (KGM). TGF-beta 1 markedly inhibited the proliferation of keratinocytes at concentrations > 1 ng/ml. Calcipotriol and desoximetasone also showed a dose-dependent cell growth inhibition in epidermal cell cultures. IL-1 alpha synthesis was greatly suppressed by calcipotriol 10(-8)-10(-6) M. EGF at 10 ng/ml, in contrast, strongly stimulated IL-1 alpha production. Neither GDF-5 nor TGF-beta 1 had a significant effect on IL-1 alpha production in keratinocyte monolayer cultures. In fibroblasts, GDF-5 induced very weak antiproliferative effects. Calcipotriol and desoximetasone also inhibited cell growth in fibroblast cultures whereas proliferation and DNA synthesis were strongly stimulated by 1 ng/ml EGF. There was, however, a contradiction between TGF-beta 1 results on fibroblasts. Whereas TGF-beta 1 increased proliferation in cell number determination and in the thymidine incorporation assay, MTT assays showed slight antiproliferative effects. Due to these controversial results, in addition cell cycle analysis was employed. TGF-beta 1 led to an increased S phase, which indicates a stimulation of cell division. The different results obtained with the MTT test suggest that TGF-beta 1 may stimulate cell division of fibroblasts not only by increasing the S phase, but also by shortening the G1 phase of the cell cycle.

Cell Cycle↗
PubMed1997

Prednicarbate biotransformation in human foreskin keratinocytes and fibroblasts.

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 x 10(-5) 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.

Administration, Topical↗
PubMed1997

Prednicarbate versus conventional topical glucocorticoids: pharmacodynamic characterization in vitro.

PURPOSE: Pharmacodynamic characterization of topical glucocorticoids as prednicarbate (PC), its metabolites prednisolone 17-ethylcarbonate (PEC) and prednisolone (PD), betamethasone 17-valerate (BMV), betamethasone (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-1 alpha-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 TNF alpha, resulting in an increased II-1 alpha synthesis. This cytokine was particularly suppressed by PC and BMV, whereas PEC, PD, DM and BM were less potent (p < or = 0.05). Since, however, the double ester PC is rapidly degraded in keratinocytes, a RNAse-protection assay of II-1 alpha 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-1 alpha and II-6 synthesis indicate proliferation and inflammation respectively. Whereas PC inhibited II-1 alpha and II-6 production in fibroblasts to a minor extent only, it was strongly reduced by the conventional glucocorticoids and PEC (p < or = 0.05). The minor unwanted effect of PC on fibroblasts was also reflected by its low influence on cell proliferation as assayed by 3H thymidine incorporation. More pronounced antiproliferative features were observed with BM, PEC and especially BMV. CONCLUSIONS: Correlating antiphlogistic effects in keratinocytes (suppression of II-1 alpha) with antiproliferative effects in fibroblasts (suppression of II-1 alpha 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.

Administration, Topical↗
PubMed1997

[Effect of keratin on the efficacy of fluconazole].

In this study we have investigated the influence of keratin on the efficacy and pharmacokinetics of fluconazole and additional azole antifungal agents. It is well known that the penetration and distribution of oral antifungals is strongly influenced by plasma protein binding. Especially, itraconazole and ketoconazole show a high binding affinity to plasma proteins, whereas fluconazole binds only with 12%. All of these antifungals, however, are accumulated in the stratum corneum of the skin. These observations have stimulated interest, if structure proteins of the skin like keratin interact with antifungals may explain of the accumulation process. Therefore we have measured the binding kinetics between keratin and the azoles. Keratin from sheep wool was degreased, purified and incubated with azole antifungals. After defined incubation periods the azoles were extracted and assayed by thin layer chromatography following UV-detection. There was a specific binding between keratin and all of the used substances. Interestingly, the binding affinity of fluconazole to keratin was much higher than to plasma proteins. Thus our observations indicate that the accumulation in the stratum corneum is a consequence of the interaction between keratin and azole derivatives.

Animals↗
PubMed1996

Topical glucocorticoids with improved risk-benefit ratio. Rationale of a new concept.

Topical glucocorticoids for dermal application were introduced more than 40 years ago and revolutionised the treatment of inflammatory skin diseases. Today these drugs are frequently administered, although systemic and local adverse drug reactions, especially skin atrophy, are feared complications of their use. This literature review evaluates the present state of topical glucocorticoid therapy for inflammatory skin diseases. Several attempts have been made to increase the safety of topical glucocorticoid treatment. With respect to conventional compounds, new application schedules, as well as new vehicles, have been proposed. New derivatives have also been synthesized, forming the novel group of nonhalogenated double-ester-type glucocorticoids. Among these latter compounds, prednicarbate and 6-methyl-prednisolone aceponate have been characterised most thoroughly. According to in vivo studies, their anti-inflammatory activity is in the order of that of betamethasone valerate (a frequently used medium potency glucocorticoid, which is obtained by halogenation of the pregnane nucleus of the steroid molecule). Furthermore, these new congeners induce less skin atrophy than conventional glucocorticoids, as determined by in vivo and in vitro studies. Qualitative and quantitative assessment of the therapeutic and adverse effects of non-halogenated double-ester-type glucocorticoids suggests an increased benefit-to-risk ratio.

Administration, Topical↗
PubMed1995

Comparative efficacy of hamamelis distillate and hydrocortisone cream in atopic eczema.

In a double-blind, randomized, paired trial lasting 14 days in 72 patients with moderately severe atopic eczema, hamamelis distillate cream (5.35 g hamamelis distillate with 0.64 mg ketone/100 g) was compared with the corresponding drug-free vehicle and 0.5% hydrocortisone cream, and reductions of the basic criteria of severe atopic eczema (delta values of the sum scores), i.e. itching, erythema and scaling, were evaluated. Thirty-six patients in each group were treated, which allowed the detection of a 10% difference between verum and control (confirmatory study). Effects were compared using Wilcoxon's test. The mean sum scores of the basic criteria of the test areas were 5.3-5.5. All treatment regimens significantly reduced itching, erythema and scaling after 1 week. Hydrocortisone proved superior to hamamelis distillate. The basic criteria scores decreased by 2.7 and 1.6, respectively. The delta values of the minor criteria and the global rating of efficacy were also used to indicate the difference between these preparations. Hamamelis distillate cream, however, did not differ from the vehicle. Mean delta values of basic criteria were 1.8 and 2.0, respectively. All preparations were well tolerated. Unwanted cutaneous reactions occurred in six patients, although due to their inflammatory nature and their confinement to vehicle-treated patients, they may not represent true adverse effects but rather a lack of efficacy. The results prove the superiority of low-dose hydrocortisone cream over hamamelis distillate cream, and the therapeutic outcome following this preparation was no better than following the base preparation. The mild, yet unmistakable anti-inflammatory effect of hamamelis cream in experimental models of inflammatory skin disease was thus not reflected by an efficacy in patients with atopic eczema greater than that obtained from the base preparation.

Administration, Topical↗
PubMed1995

Discrimination of the toxic potential of chemically differing topical glucocorticoids using a neutral red release assay with human keratinocytes and fibroblasts.

In inflammatory skin disease, hydrocortisone and prednisolone double esters are about equipotent to conventional medium potency topical glucocorticoids, such as betamethasone valerate. Local adverse effects, in particular skin atrophy, are a potential problem with topical glucocorticoids. Recently, cell cultures have shown promise as a means of assessing local tolerance. To investigate the toxic potential of hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone aceponate, prednicarbate, triamcinolone acetonide, betamethasone valerate and desoximethasone, human keratinocytes and fibroblasts were exposed to these agents in vitro, using a modified neutral red release assay. In addition, the morphology of these cells was assessed by light microscopy. Although all the topical glucocorticoids tested proved toxic to both cell types, there were major differences between glucocorticoids in their effect on fibroblasts. Hydrocortisone and the non-halogenated double-ester-type glucocorticoids were less toxic than the conventional medium potency topical glucocorticoids tested (betamethasone valerate and desoximethasone). In particular, hydrocortisone aceponate was less toxic than betamethasone valerate (P < or = 0.05). In general, the effect of topical glucocorticoids on the cells, based on neutral red release, was more marked with keratinocytes than with fibroblasts. Although the ranking order with respect to the toxic potential was similar, a clear-cut difference was not observed between non-halogenated double-ester-type glucocorticoids and betamethasone valerate. Morphological changes due to glucocorticoid exposure followed the same pattern with both keratinocytes and fibroblasts. The neutral red release assay is able to discriminate between the cytotoxic effects of chemically differing topical glucocorticoids on human keratinocytes and fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1994

Liposomal tretinoin for uncomplicated acne vulgaris.

Frequently occurring skin irritancy and flare-up reactions impede the use of topical tretinoin for acne vulgaris due to poor patient compliance. Liposome encapsulation improves penetration into the skin and local tolerability in animals. We investigated efficacy and local tolerability of liposomal tretinoin in man. In a double-blind study 20 patients with uncomplicated acne vulgaris received liposomal tretinoin (0.01%) on one side of the body and a commercial gel preparation with either 0.025% or 0.05% on the other once daily for 10 weeks. Comedones and papules/pustules were counted every 2 (-4) weeks. Then also redness, scaling, and burning were rated according to a four-point scale. Moreover, the patients noted skin irritancy in a diary on a daily base. With conventional tretinoin the gels were equally efficacious and equally well tolerated. Liposomal tretinoin also appeared equipotent to the reference gels. There may even have been a slightly more rapid clearing of comedones following the liposome preparation. With respect to skin irritancy, however, liposomal tretinoin was superior. As rated by the patients, liposome encapsulated tretinoin induced less burning (mean cumulative score 2.7 +/- 1.2) than the 0.025% gel (16.1 +/- 7.1) and the 0.05% gel (9.7 +/- 4.1) gel and less erythema (1.8 +/- 0.7) than the 0.025% gel (11.4 +/- 3.8; (P < 0.05). Liposomal tretinoin was also better tolerated according to the rating by the investigator. Liposomal encapsulation of tretinoin allows reduction of the concentration of the active agent without a decline in efficacy for acne vulgaris. Since local tolerability is thus increased, liposomal tretinoin should favor the acceptance of this treatment by the patient.

Acne Vulgaris↗
PubMed1993

Influence of topical erythromycin preparations for acne vulgaris on skin surface pH.

Topical erythromycin is a standard regimen for inflammatory acne vulgaris because of its action against Propionibacterium acnes. Changes in P. acnes colonization are inducible by long-lasting changes of skin surface pH. Therefore, the influence of six erythromycin preparations with approximative pH values of 7.5 (preparation A) to 10.2 (C) on the skin surface pH was evaluated in healthy volunteers using a cross-over design. Following a 14-day run-in period, a constant skin surface pH (5.0) was found. Ten subjects received single doses 2-3 days apart; 20 volunteers applied preparations A and C for 28 days. Single doses of preparations A and E (pH 8.0) increased skin pH to 6.99 and 8.61, respectively, at 15 min; it then gradually declined. The other preparations induced only a minor rise of short duration. At the end of the long-term application, the skin surface pH amounted to 5.73 (A) and 5.39 (C). There was no correlation between the effect on skin surface pH and the approximative pH of the preparations. A close relation of single-dose and long term-effects was observed, however. The skin surface pH during the application of preparation A is high enough to increase P. acnes growth about fourfold as compared with normal skin and thus may counteract the antibacterial effect. Clinical relevance should be evaluated in a controlled clinical trial comparing the efficacy of preparation A with that of preparation C.

Acne Vulgaris↗
PubMed1993

Anti-inflammatory activity of hamamelis distillate applied topically to the skin. Influence of vehicle and dose.

The anti-inflammatory activity of hamamelis distillate has been evaluated with respect to drug concentration (0.64 mg/2.56 mg hamamelis ketone/100 g) and the effect of the vehicle (O/W emulsion with/without phosphatidylcholine (PC) in an experimental study. The effects were compared with those of chamomile cream, hydrocortisone 1% cream and 4 base preparations. Erythema was induced by UV irradiation and cellophane tape stripping of the horny layer in 24 healthy subjects per test. Skin blanching was quantified by visual scoring and chromametry. Drug effects were compared with one another and with an untreated control area, as well as with any action due to the vehicle. UV-induced erythema at 24 h was suppressed by low dose hamamelis PC-cream and hydrocortisone cream. Hydrocortisone appeared superior to both hamamelis vehicles, hamamelis cream (without PC) and chamomile cream. The latter preparation was also less potent than hamamelis PC-cream. Erythema 4 to 8 h after the stripping of the horny layer was suppressed by hydrocortisone (P < or = 0.05). Inflammation was also less pronounced following low dose hamamelis PC-cream and chamomile cream. Hamamelis PC-cream, however, appeared less potent than hydrocortisone. In general, visual scoring was more discriminatory than chromametry. The results have demonstrated an anti-inflammatory activity of hamamelis distillate in a PC-containing vehicle. A fourfold increase of drug concentration, however, did not produce an increase in activity.

Administration, Topical↗
PubMed1993

Prednicarbate activity and benefit/risk ratio in relation to other topical glucocorticoids.

BACKGROUND: Nonhalogenated double esters of prednisolone or hydrocortisone applied topically to the skin have a low atrophogenic potential. However, activity and benefit/risk ratio and therefore the superiority over conventional topical glucocorticoids are not well defined. METHODS: The activities of cream preparations with prednicarbate (0.025% to 0.25%), hydrocortisone aceponate, and hydrocortisone buteprate (0.1%) are compared to the effects of betamethasone 17-valerate (0.1%), hydrocortisone (1%), and two drug-free vehicles in 60 healthy volunteers. Test models are the skin blanching assay (occluded and nonoccluded mode), ultraviolet-induced erythema, and an irritant (sodium dodecyl sulfate) dermatitis. The benefit/risk ratio is derived from the activity in the former models and the reduction of skin thickness as determined previously. RESULTS: Prednicarbate activity increases in a dose-dependent manner. Prednicarbate, 0.25%, and the hydrocortisone double esters appear to be equipotent to betamethasone 17-valerate in the skin blanching test and the ultraviolet-erythema test, but superior to hydrocortisone and the vehicles. Prednicarbate and its vehicle, however, do not reverse irritant dermatitis. The benefit/risk ratios of prednicarbate and hydrocortisone aceponate exceed those with betamethasone 17-valerate. CONCLUSIONS: Prednicarbate and hydrocortisone aceponate are intermediate potent glucocorticoids that are superior to betamethasone 17-valerate because of the improved benefit/risk ratio. Patients with severe atopic dermatitis and those who relapse frequently should profit from the treatment with these newer glucocorticoids.

Administration, Topical↗
PubMed1993

Treatment of tinea unguium with medium and high doses of ultramicrosize griseofulvin compared with that with itraconazole.

Toenail tinea is a very recalcitrant dermatosis. Griseofulvin at > or = 500 mg/day is the current medication of choice, but it is minimally successful. In a controlled open trial ultramicrosize griseofulvin (UMSG) at doses of 660 and 990 mg/day was compared with itraconazole at 100 mg/day in 109 patients. At 4-week intervals, the patients were evaluated for their clinical and mycological statuses and adverse reactions. Treatment was given for up to 18 months. Compliance was checked by tablet counting. Response (cure, partial cure, marked improvement) was analyzed by the intent-to-treat method. Cured and partially cured patients were followed up. Except for one early dropout, the toenails (mean, 6 to 7) were involved. Cure or partial cure was found in 6% (UMSG at 660 mg), 14% (UMSG at 990 mg), and 19% (itraconazole at 100 mg) of patients (P = 0.2097); marked improvement was found in 36, 44, and 39% of patients in the three treatment groups, respectively. Most patients had to be treated for 18 months. Failure was related to short medication periods (adverse drug reactions, dropout). While stable cure was not obtained with UMSG at 660 mg, the higher dose of UMSG and itraconazole gave stable cures in the other patients. Side effects of nausea, diarrhea, and headache were found in 20, 26, and 11 patients, respectively (P = 0.0028), and the numbers in whom medication had to be discontinued differed, too (P = 0.0137). While there was no major difference with glutamic-pyruvic transaminase and gamma-GT, total and low-density lipoprotein cholesterol levels declined slightly in the itraconazole group (P = 0.0357 and P = 0.0639, respectively, at 3 months). More than 70% of the patients had an average compliance of > or = 90%; four patients (two dropouts) were poor compliers. In conclusion, it appears questionable whether griseofulvin can continue to be considered the "gold standard" in the treatment of toenail tinea. At present, itraconazole at 100 mg shows better efficacy and is better tolerated.

Adult↗
PubMed1993

Pharmacokinetic optimisation of oral antifungal therapy.

The range of oral antifungal therapy has been expanded recently by the introduction of itraconazole, and terbinafine. These agents have a broader spectrum of activity than griseofulvin and flucytosine, and induce less liver toxicity than ketoconazole. Treatment with these agents may be optimised by application of pharmacokinetic principles. Griseofulvin, ketoconazole and itraconazole should be administered with food to ensure adequate absorption. Maximal absorption of griseofulvin is achieved by administration of the drug as a solid solution in polyethylene glycol. Absorption of azole antifungal agents is impaired by high gastric pH, which is observed in some patients with acquired immunodeficiency syndrome. It is also impaired by frequent vomiting, which commonly occurs in patients with neutropenia. Furthermore, antacids, H2-antagonists and sucralfate interfere with absorption of ketoconazole. The newer oral antifungals are more slowly eliminated and associated with less pronounced drug interactions than ketoconazole. As with ketoconazole, itraconazole and fluconazole influence cyclosporin metabolism. These effects are of clinical relevance and necessitate cyclosporin dosage reduction. However, the cyclosporin dosage reduction required during coadministration of itraconazole and fluconazole (50 to 55%) is less than that required when ketoconazole is concomitantly administered (85%). Monitoring of cyclosporin concentrations during coadministration with these agents is necessary to avoid nephrotoxicity. Drug monitoring is also advisable when phenytoin, carbamazepine or rifampicin (rifampin) are administered concomitantly with azoles, due to a mutual influence on drug metabolism. The antifungal activity of itraconazole is not related exclusively to free drug concentrations. Therefore, the low protein binding of fluconazole does not place this agent at an advantage over itraconazole in the treatment of fungal meningitis. However, terbinafine may be superior to itraconazole for the treatment of tinea unguium, another recalcitrant fungal disease, because terbinafine more rapidly penetrates the nail plate. During repeated use, itraconazole concentrations increase slowly in the nail plate. Steady-state concentrations are reached in the stratum corneum only after several weeks' administration. Following cessation of treatment, terbinafine, itraconazole and ketoconazole concentrations in keratinised tissues decline slowly. This allows a short duration of drug treatment. Some clinical trials suggest that low concentrations of flucytosine, griseofulvin and itraconazole are associated with treatment failure. Flucytosine-induced myelotoxicity also appears to be concentration dependent. This adverse reaction may be caused by fluorouracil (which is produced by metabolism of flucytosine by enterobacillary flora in the gut) rather than by the parent compound.

Adolescent↗
PubMed1992

Topical glucocorticoids with improved benefit/risk ratio: do they exist?

Topical glucocorticoids are still among the dermatologicals most frequently used. This is due to their undebatable potency in inflammatory skin disease. Their use is limited by the fear of side effects both systemic and topical, especially skin atrophy. Hence, congeners with an increased benefit-risk ratio are urgently needed and research on new drugs no longer focuses on more active drugs but safer ones. Only recently, evidence has been forwarded that the goal is realistic. Some new glucocorticoids, especially the nonfluorinated double-ester type such as prednicarbate, appear promising. In fact, they seem to affect fibroblast growth in vitro as well as skin thickness in vivo less than equipotent conventional glucocorticoids. Pertinent findings in humans have been obtained with the use of ultrasound equipment. The relevant aspects of chemistry, pharmacology, clinical benefits, and toxicology of the various glucocorticoids old and new are reviewed, as are potential future alternatives.

Administration, Topical↗