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M Schäfer-Korting

Publications and source records attributed to M Schäfer-Korting.

88 records · Page 5Linked to original sources
PubMed1982

Intraindividual variations of 8-methoxypsoralen plasma levels.

Intraindividual variations of 8-methoxypsoralen (8-MOP) plasma levels were investigated. On at least 3 consecutive days of treatment 8-MOP levels were determined 2 h following the administration of 0.56-0.82 mg/kg b.w. On day 1 a complete plasma level-time profile was obtained. Interindividually, 8-MOP plasma levels varied from 0-654 ng/ml. Intraindividual variation was considerably less being 1.2-5.3-fold. In one patient who showed a lower absorption rate of 8-MOP plasma levels varied from 0-126 ng/ml. There was a rather close correlation (r = 0.81) of the variation of 8-MOP plasma levels (determined as the ratio of highest to lowest plasma level) and mean plasma level, intraindividual variation decreasing exponentially with increasing 8-MOP plasma levels. Parameters determining variation of 8-MOP plasma levels are the intrinsic hepatic clearance, liver blood flow, and possibly the absorption of the drug from gastrointestinal tract. To keep intraindividual variation as low as possible ingestion of the drug together with a standardized meal is suggested. Drugs interfering with hepatic metabolism or liver blood flow should be avoided.

Adult↗
PubMed1982

Determination of 8-methoxypsoralen levels in plasma and skin suction blister fluid by a new sensitive fluorodensitometric method.

An improved fluorodensitometric assay for the determination of 8-methoxypsoralen (8-MOP) in plasma is described. Because of its low limit of detection (below 1 ng/spot) this method is suitable to determine the drug in skin suction blister fluid, too. The standard deviation of the procedure is 6.4% or less. Plasma and skin blister fluid levels of 8-MOP are determined 2 h following oral administration of 40-60 mg 8-MOP. They range from 0-239 ng/ml and 0-163 ng/ml, respectively. A rather close correlation (r = 0.91) between these two parameters could be observed. Thus, in cases with relatively high plasma levels sufficient skin levels can be predicted. If further investigations would prove, however, that a distinct concentration threshold required for therapeutic success exists--and recent experiments with fibroblast cultures imply that--skin blister fluid level determinations would seem highly desirable when plasma levels let us expect skin levels in the critical range. In general determination of 8-MOP skin blister fluid levels can be looked upon as a model for the evaluation of drug skin levels after systemic application in man.

Adult↗
PubMed1982

Does cantharides blister fluid provide access to the peripheral compartment?

The pharmacokinetics of bendroflumethiazide (BFT) was investigated following the oral administration of 10 mg to 3 healthy volunteers. Each subject participated twice in the study. BFT was determined in plasma and cantharides blister fluid from 1/2 to 30 h post administration. Blister fluid was obtained from blisters 10-22 h old. Plasma levels were fitted to a tri-exponential equation and the concentration of the drug in the peripheral compartment was calculated from the microscopic rate constants. In 5 of 6 cases investigated, cantharides blister fluid levels paralleled the concentration of the drug in the peripheral compartment. The mean blister fluid levels exceeded the calculated concentration in Compartment 2 1.46 fold. In one case, the blister fluid level paralleled the plasma level. This subject clearly differed from the others as more than 10 h were required for blister formation in her. The results suggest that following the administration of BFT, cantharides blister fluid behaves as part of the peripheral compartment. The possible value of studying blister fluid levels in pharmacokinetic investigations is discussed.

Adult↗
PubMed1982

Pharmacokinetics of bendroflumethiazide alone and in combination with propranolol and hydralazine.

Bendroflumethiazide (Bft) was administered to 6 healthy subjects at 3 different dose levels (2.5, 5 and 10mg) in a cross-over design, either as capsules (2.5mg) or as tablets (5mg). Its pharmacokinetics were evaluated then and following administration of a fixed combination of Bft and propranolol and hydralazine to a further 7 volunteers. Plasma and urinary concentrations of Bft were determined by a new fluorimetric - thin-layer chromatography procedure. Peak plasma levels occurred after 2-3h and averaged 15, 27 and 45 microgram/l in the three dose groups. Areas under the plasma concentration - time curves (AUC0 leads to 12), which were 75, 147 and 250 microgram 1(-1)h respectively, and cumulative urinary recovery (20%) were independent of the dose administered and the type of formulation. Thus Bft kinetics proved to be linear within the dose range evaluated. The plasma clearance was calculated to be 505 ml/min, renal clearance 108 ml/min and nonrenal clearance 396 ml/min. Bioavailability of Bft was not altered following administration of the fixed combination. The amount of propranolol found in the circulation did not change, whereas that of hydralazine (determined as apparent hydralazine) increased by 59% when the fixed combination was administered.

Adult↗
PubMed1981

Interaction of atenolol with furosemide and calcium and aluminum salts.

Six healthy subjects were treated with 100 mg atenolol. After a therapy-free interval of 4 wk the same subjects received the same dose of atenolol with furosemide, 40 mg, with calcium (as the lactate gluconate and carbonate), 500 mg, or with aluminum hydroxide, 5.6 gm. Atenolol alone and in combination was administered first as a single oral dose; a long-term 6-day treatment began 48 hr later. Addition of furosemide did not influence atenolol kinetics, but aluminum hydroxide led to an insignificant reduction (P greater than 0.05) of mean peak plasma levels of about 20% and of the area under the plasma concentration-time curve (AUC -infinity) from 5818 to 4353 ng ml-1 hr (P greater than 0.05). Calcium altered atenolol kinetics distinctly mean peak plasma levels of atenolol fell 51% (P less than 0.001), AUC0-infinity fell from 5818 to 3935 ng ml-1 hr (P less than 0.01) and elimination half-life (t1/2) increased to a mean of 11.0 hr (compared to 6.2 hr with atenolol alone). The prolongation of t1/2 induced by calcium coadministration led to atenolol cumulation during the long-term dosage. Twelve hours after atenolol, 100 mg, and calcium, 500 mg, exercise tachycardia was lower than with atenolol alone (P less than 0.001). During the 4-wk treatment in six hypertensive patients, blood pressure values of those on atenolol alone were not different from those on the combination therapies (P greater than 0.05).

Adult↗
PubMedDate not supplied

Influence of serum protein binding on the in vitro activity of anti-fungal agents.

Historically it has been assumed that the pharmacological effect is related to the free drug concentration. In exposing Candida albicans to itraconazole and ketoconazole serum concentration-time profiles, however, antifungal activity was not diminished despite intense albumin binding. The relevance of serum protein binding was further investigated, by in vitro susceptibility testing of C. albicans (40 clinical isolates) and Trichophyton rubrum (ten strains) against antifungal agents using microdilution tests allowing the determination of IC30- and MIC-values. The range of serum protein binding ranges from 11% with fluconazole to > 99% with itraconazole and terbinafine. The ratios of IC30- and MIC-values with and without serum protein (albumin, alpha- and gamma-globulin, human plasma) were related to the loss of susceptibility expected according to the free-drug hypothesis. A difference in the albumin effect with the test strains was not observed. With most antifungals including terbinafine, the activity declined as expected. IC30- and MIC-ratios for miconazole were 7 and 13 (observed) vs. 12-20 (expected), for fluconazole 1.5 and 3.5 vs. 1.1, for amphotericin B 10 vs. 11-20, for griseofulvin 3.6 vs. 4, and for terbinafine 61 vs. 100. Itraconazole activity, however, was not diminished by albumin (expected ratio 286), and ketoconazole effects decreased less than expected (ratio 5-15, expected about 100). alpha-globulin, but not gamma-globulin induced a major loss in anti-Candida activity of itraconazole and ketoconazole, which is paralleled by a decline in ketoconazole (but not itraconazole) activity due to plasma. With the other antifungals (except for ciclopiroxolamine) IC30-values for C. albicans increased, too. Due to the complete inhibition of T. rubrum growth by gamma-globulin, this species proved unsuitable for studying the gamma-globulin effects. The present study demonstrates that the effects of intense protein binding on drug activity are only partly predictable from binding studies in vitro.

Antifungal Agents↗
PubMedDate not supplied

Clinical use of oral nystatin in the prevention of systemic candidosis in patients at particular risk.

Systemic candidosis is currently a major concern among certain groups of patients at particular risk because of recent treatment modalities. To prevent spread of Candida albicans, in particular, from the orogastrointestinal tract antimycotic treatment would appear beneficial. So far, however, suitable drugs are rare. Polyenes, and in particular oral nystatin, are the main ones considered so far. More recently, the oral azoles have provided therapeutic alternatives. In this review the current role of nystatin and, in particular nystatin tablets, which are better accepted than suspensions at higher dose levels, is described, focusing on efficacy and safety as determined in controlled trials. Recent evidence suggests that oral application of nystatin tablets can be considered both efficacious and safe in the appropriate context. The relative potency of oral nystatin and systemic azoles, particularly ketoconazole and fluconazole, awaits final determination.

Administration, Oral↗
PubMedDate not supplied

Cutaneous inflammation and proliferation in vitro: differential effects and mode of action of topical glucocorticoids.

The nonhalogenated double ester of prednisolone, prednicarbate (PC), is the first topical glucocorticoid with an improved benefit/risk ratio verified clinically and in vitro. To evaluate if this is due to unique characteristics of this steroid, a new compound created according to an identical concept, prednisolone 17-ethylcarbonate, 21-phenylacetate (PEP), and the new halogenated monoester desoximetasone 21-cinnamate (DCE) were tested and compared to PC, desoximetasone (DM) and betamethasone 17-valerate (BMV). Isolated foreskin keratinocytes served for in vitro investigations of anti-inflammatory processes in the epidermis, fibroblasts of the same origin were used to investigate the atrophogenic potential. Inflammation was induced by TNFalpha, resulting in an increased interleukin 1alpha (Il-1alpha) synthesis. As quantified by ELISA, all drugs significantly reduced Il-1alpha production. But PC and BMV appeared particularly potent, followed by DM and the two new congeners, which revealed minor anti-inflammatory activity. Glucocorticoid esters including PEP are rapidly degraded in keratinocytes (85% within 12 h). Hence, a ribonuclease protection assay of Il-1alpha mRNA was performed allowing short incubation times and thus minimizing biodegradation. This assay confirmed the anti-inflammatory potency of native PC and BMV. In contrary DCE and PEP did not reduce Il-1alpha mRNA to a significant extent. Therefore PEP acts as a prodrug only. In fibroblasts, Il-1alpha and Il-6 syntheses indicate proliferation and inflammation, respectively. Whereas PC and PEP inhibited Il-1alpha and Il-6 production in fibroblasts only to a minor extent, cytokine synthesis was strongly affected by the conventional glucocorticoids BMV and DM, but also by DCE. The minor unwanted effect of PC and PEP on fibroblasts was also reflected by their low influence on cell proliferation as derived from (3)H-thymidine incorporation. Again, more pronounced antiproliferative features were seen with the halogenated glucocorticoids. In the following, the correlation between antiphlogistic effects in keratinocytes (suppression of Il-1alpha) and antiproliferative effects in fibroblasts (suppression of Il-1alpha and Il-6; (3)H-thymidine incorporation) was analyzed. Here, PC is revealed as the only glucocorticoid with an improved benefit/risk ratio. Native PEP is shown to be almost ineffective and DCE presents exactly the opposite features of PC. It is tempting to speculate if this is due to different glucocorticoid receptor subtypes or different signaling pathways in keratinocytes and fibroblasts.

Administration, Topical↗
PubMedDate not supplied

Transcriptional activity of potent glucocorticoids: relevance of glucocorticoid receptor isoforms and drug metabolites.

As compared to standard glucocorticoids (GC), prednicarbate (PC) is favorable in the treatment of eczema due to its high benefit/risk ratio. The remarkable anti-inflammatory effects of PC are in strong contrast to its reported low glucocorticoid receptor (GR) binding affinity. In transfected COS-7 cells we related the transcriptional potencies of PC, its metabolites and conventional GC to their receptor binding properties. Moreover, the expression pattern of the human GR isoform hGRalpha and its mutual dominant negative inhibitor hGRbeta in skin cells have been investigated as well as the influence of hGRbeta on receptor binding and transactivation. hGRalpha mRNA and protein was largely overexpressed in skin cells. hGRbeta showed no influence on hGRalpha binding and transactivation. Concentration response curves indicated the greater transactivation potency of betamethasone 17-valerate followed by dexamethasone and prednisolone 17-ethylcarbonate. Native PC appeared almost as potent as dexamethasone. With both a strong correlation was observed between transactivation and GR binding.

Animals↗
PubMedDate not supplied

Testosterone metabolism in human skin cells in vitro and its interaction with estradiol and dutasteride.

Since the limited knowledge of cutaneous drug metabolism can impair the development of specifically acting topical dermatics and transdermal application systems, the cell-type-specific androgen metabolism in human skin and its inhibition by drugs were investigated. Cultured human foreskin and scalp skin keratinocytes and fibroblasts as well as occipital scalp dermal papilla cells (DPC) were incubated with testosterone 10(-6) and 10(-8)M alone and in the presence of 17alpha-estradiol, 17beta-estradiol or dutasteride for 24 h. Androgens extracted from culture supernatants were subjected to thin-layer chromatography and quantified by beta-counting. In keratinocytes and DPC, dihydrotestosterone (DHT) was only formed to a low extent while androstenedione was the main metabolite. In fibroblasts, DHT formation was pronounced following 10(-8)M testosterone. Dutasteride 10(-8)M completely suppressed 5alpha-dihydro metabolite formation. 17alpha-Estradiol and 17beta-estradiol at nontoxic concentrations decreased 17-ketometabolites. Human skin regulates testosterone action by cell-type-specific activation or deactivation. Effects of 17alpha-estradiol in androgenetic alopecia are not due to 5alpha-reductase inhibition. Dutasteride may be useful in acne and androgenetic alopecia.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMedDate not supplied

Tazarotene: therapeutic strategies in the treatment of psoriasis, acne and photoaging.

Tazarotene is a member of the new generation of receptor-selective, synthetic retinoids for the topical treatment of mild to moderate plaque psoriasis, acne vulgaris and photoaging. Though they are effective in monotherapy, clinical studies with a focus on novel combination treatments and a comparison of different agents for these skin disorders are accumulating. The concomitant use of tazarotene with a mid-potency or high-potency corticosteroid enhances the efficacy in psoriatic plaques and reduces the risk of steroid-induced skin atrophy. Combining phototherapy with adjunctive tazarotene accelerates the clinical response and reduces the cumulative UVB or PUVA exposure load. Tazarotene applied once daily is superior to adapalene monotherapy in acne vulgaris and is efficacious in the treatment of photodamage. Novel therapeutic regimens such as short-contact therapy have been developed for both acne and psoriasis in order to diminish the major adverse events like pruritus, burning, local skin irritation and erythema.

Acne Vulgaris↗
PubMedDate not supplied

Hyaluronic acid in the treatment and prevention of skin diseases: molecular biological, pharmaceutical and clinical aspects.

The glycosaminoglycan hyaluronic acid (HA), or hyaluronan, is a major component of the extracellular matrix of skin, joints, eye and many other tissues and organs. In spite of its simple structure, HA demonstrates remarkable rheological, viscoelastic and hygroscopic properties which are relevant for dermal tissue function. Biological activities in skin, however, are also due to its interaction with various binding proteins (hyaladherins). Due to an influence on signaling pathways, HA is involved in the wound-healing process and scarless fetal healing. Increased HA concentrations have been associated with inflammatory skin diseases. In clinical trials, topical application of HA improved wound healing; in particular, acute radioepithelitis, venous leg ulcers or diabetic foot lesions responded to HA treatment. Moreover, as a topical drug delivery system for diclofenac, an HA gel has recently been approved for the treatment of actinic keratoses. Finally, chemical modifications led to new HA derivates and biomaterials, which may be introduced into therapy in the future. Therefore, ongoing research offers new horizons for the therapeutic use of this glycosaminoglycan which has been regarded as an inert structural component until recently.

Animals↗
PubMedDate not supplied

Safety and efficacy of fluticasone propionate in the topical treatment of skin diseases.

Fluticasone propionate - the first carbothioate corticosteroid - has been classified as a potent anti-inflammatory drug for dermatological use. It is available as 0.05% cream and 0.005% ointment formulations for the acute and maintenance treatment of patients with dermatological disorders such as atopic dermatitis, psoriasis and vitiligo. This glucocorticoid is characterized by high lipophilicity, high glucocorticoid receptor binding and activation, and a rapid metabolic turnover in skin. Although skin blanching following fluticasone propionate exceeds that of corticosteroids of medium strength, several clinical trials demonstrate a low potential for cutaneous and systemic side-effects, even in difficult-to-treat areas like the face, the eyelids and intertriginous areas. Even among paediatric patients with atopic dermatitis, fluticasone propionate proved to be safe and effective. These pharmacological and clinical properties are reflected by the high therapeutic index of this glucocorticoid.

Administration, Cutaneous↗
PubMedDate not supplied

Pharmacokinetics of griseofulvin in blood and skin suction blister fluid of rats.

The penetration of griseofulvin to its site of action was investigated in the rat using subepidermal blisters induced by suction as a model. Griseofulvin was administered iv at a dose of 20 mg/kg after which blood, suction blister fluid (SBF), and skin tissue were sampled over a 300-min time period. The blood level/time course can be described by a two-compartment model. During the terminal phase, concentrations of drug in blood, SBF, and cutis declined in parallel, with respective half-lives of 71.0, 70.4, and 74.6 min. In SBF, maximum concentrations (2.35 +/- 0.36 micrograms/ml) were obtained 60 min postinjection, drug levels increased until the concentrations of unbound griseofulvin in SBF and plasma were identical. Time to peak concentration in cutis was shorter (20 min; 13.9 +/- 0.5 micrograms/ml). As the dermatophytes are located in the horny layer, the determination of griseofulvin in SBF seems to be a more suitable assay for determining the griseofulvin level profile at its site of action. In addition, the level of unbound, and thus active, griseofulvin in SBF was severalfold lower than the concentration of total drug in excised skin tissue. Up to now, the latter value has been considered to indicate that the concentration of griseofulvin in the skin is comparable to the in vitro sensitivity of dermatophytes. The present results show that this seems to be no longer justified.

Albumins↗