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Hans Christian Korting - One of the best experts on this subject based on the ideXlab platform.
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Esterase activity in excised and reconstructed human skin--biotransformation of Prednicarbate and the model dye fluorescein diacetate.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2012Co-Authors: Franzisca Marie Bätz, Hans Christian Korting, Wiebke Klipper, Frank Henkler, Robert Landsiedel, Andreas Luch, Uwe Von Fritschen, Günther Weindl, Monika Schäfer-kortingAbstract:Reconstructed human epidermis (RHE) is used in non-animal testing for hazard analysis and reconstructed human skin (RHS) gains growing interest in preclinical drug development. RHE and RHS have been characterised regarding their barrier function, but knowledge about biotransformation capacity in these constructs and in human skin remains rather poor. However, metabolising enzymes can be highly relevant for the efficacy of topical dermatics as well as genotoxicity and sensitisation. We have compared the esteratic cleavage of the prednisolone diester Prednicarbate and the enzyme kinetic parameters (Vmax and S0.5) of the model substrate fluorescein diacetate (FDA) in commercially available RHS and RHE with excised human skin and monolayer cultures of normal and immortalised human keratinocytes and of fibroblasts. Formation of the main metabolite prednisolone and of fluorescein ranked as: RHS~RHE>excised human skin and keratinocytes>fibroblasts, respectively. Because of the aromatic probe, however, Vmax of FDA cleavage did not show a linear relationship with Prednicarbate metabolism. In conclusion, RHE and RHS may be useful to quantitatively address esterase activity of human skin in drug development and hazard analysis, although an increased activity compared to native human skin has to be taken into account.
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Topical fluticasone propionate: intervention and maintenance treatment options of atopic dermatitis based on a high therapeutic index
Journal of the European Academy of Dermatology and Venereology : JEADV, 2011Co-Authors: Hans Christian Korting, C SchöllmannAbstract:Fluticasone propionate (FP), a medium potent glucocorticoid (class III) of carbothioate nature with a favourable benefit/risk ratio, has emerged as a standard medication for the topical treatment of inflammatory skin disorders, in particular atopic dermatitis (AD). FP is available as a 0.05% cream and a 0.005% ointment formulation. The glucocorticoid is characterized by high lipophilicity, high affinity binding to the glucocorticoid receptor and a rapid hepatic biotransformation. Though skin blanching following topical application of FP surpasses that given with glucocorticoids of medium strength, clinical trials show a low potential of FP for local and systemic adverse effects. Even in paediatric patients with AD as well as in difficult-to-treat areas like face, eyelids and intertriginous areas, FP proved to be both effective and safe. Thus, the therapeutic effects of FP clearly outweigh the unwanted effects. Correspondingly, a therapeutic index of 2.0 can be attributed to this glucocorticoid. In this respect, topical FP does not differ from other topical glucocorticoids with increased benefit-to-risk ratio, e.g. Prednicarbate, methylprednisolone aceponate and mometasone furoate. However, randomized controlled trials do not only support conventional intervention but also innovative maintenance treatment.
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The impact of skin viability on drug metabolism and permeation -- BSA toxicity on primary keratinocytes.
Toxicology in vitro : an international journal published in association with BIBRA, 2005Co-Authors: Annekathrin Haberland, Burkhard Kleuser, Hans Christian Korting, C. Santos Maia, S. Schreiber, M.k. Rübbelke, Martin Schaller, I. Schimke, Monika Schäfer-kortingAbstract:For testing cutaneous absorption of drugs, ingredients of cosmetics and also for risk assessment of industrial compounds predictable in vitro test protocols are under investigation using excised skin or reconstructed human epidermis. Since the metabolizing enzymes expressed by viable skin can influence the absorption behaviour of substances by changing their structure and thereby their physicochemical characteristics, the metabolic capacity should be considered in the design of the test protocols of compounds susceptible to metabolism. Then data, generated using viable reconstructed epidermis may reflect the in vivo situation. Interestingly, bovine serum albumin (BSA) commonly used in receptor media in permeation studies to facilitate solubility of highly lipophilic substances strongly inhibited the metabolism of topically applied Prednicarbate in reconstructed epidermis. Here, we show that 5% BSA is toxic to reconstructed epidermis and keratinocytes which was consistent with the earlier findings. While media toxicity (deficiency media) was at least partly the cause of both apoptotic and necrotic processes in keratinocytes, BSA only slightly increased the rate of necrotic cells. Moreover, caspase inhibitors did not reduce BSA toxicity. Yet, the results show that BSA toxicity on keratinocytes has to be carefully considered if this protein is used in permeation studies with reconstructed epidermis.
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Glucocorticoid entrapment into lipid carriers — characterisation by parelectric spectroscopy and influence on dermal uptake
Journal of controlled release : official journal of the Controlled Release Society, 2004Co-Authors: R. Sivaramakrishnan, Hans Christian Korting, Wolfgang Mehnert, C. Nakamura, K.d. Kramer, Monika Schäfer-kortingAbstract:Topical glucocorticoids such as betamethasone 17-valerate (BMV) and Prednicarbate (PC) are an important therapeutic option in atopic eczema. To reduce the risk of dermal atrophy, we aimed at BMV incorporation into solid lipid nanoparticles (SLN) for epidermal targeting using various lipids and emulsifiers corresponding to previous work on PC. Cutaneous absorption into excised human skin was compared to the one with a cream. While Compritol-based particles increased BMV uptake about fourfold we failed, however, to obtain epidermal targeting. To obtain insight into the location of active substance relative to the carrier, we used the recently optimised method of parelectric spectroscopy (PS). In fact, we were able to study electric dipole movements in the broad field of a frequency span from 0.1 to 100 MHz demonstrating that glucocorticoids are attached to the particle surface but are not incorporated into the lipid matrix. With BMV, the loading capacity of the particle surface lies clearly below the usual concentration of 0.1% which is not the case with PC. An adequate association of drug and carrier is essential for epidermal targeting. Parelectric spectroscopy provides insight into the interaction between drug and lipidic carrier.
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Transcriptional activity of potent glucocorticoids: relevance of glucocorticoid receptor isoforms and drug metabolites.
Skin pharmacology and applied skin physiology, 2003Co-Authors: I. Spika, Burkhard Kleuser, Hans Christian Korting, Stefanie Hammer, Monika Schäfer-kortingAbstract: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.
Monika Schäfer-korting - One of the best experts on this subject based on the ideXlab platform.
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Esterase activity in excised and reconstructed human skin--biotransformation of Prednicarbate and the model dye fluorescein diacetate.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2012Co-Authors: Franzisca Marie Bätz, Hans Christian Korting, Wiebke Klipper, Frank Henkler, Robert Landsiedel, Andreas Luch, Uwe Von Fritschen, Günther Weindl, Monika Schäfer-kortingAbstract:Reconstructed human epidermis (RHE) is used in non-animal testing for hazard analysis and reconstructed human skin (RHS) gains growing interest in preclinical drug development. RHE and RHS have been characterised regarding their barrier function, but knowledge about biotransformation capacity in these constructs and in human skin remains rather poor. However, metabolising enzymes can be highly relevant for the efficacy of topical dermatics as well as genotoxicity and sensitisation. We have compared the esteratic cleavage of the prednisolone diester Prednicarbate and the enzyme kinetic parameters (Vmax and S0.5) of the model substrate fluorescein diacetate (FDA) in commercially available RHS and RHE with excised human skin and monolayer cultures of normal and immortalised human keratinocytes and of fibroblasts. Formation of the main metabolite prednisolone and of fluorescein ranked as: RHS~RHE>excised human skin and keratinocytes>fibroblasts, respectively. Because of the aromatic probe, however, Vmax of FDA cleavage did not show a linear relationship with Prednicarbate metabolism. In conclusion, RHE and RHS may be useful to quantitatively address esterase activity of human skin in drug development and hazard analysis, although an increased activity compared to native human skin has to be taken into account.
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In vitro skin absorption and drug release - a comparison of six commercial Prednicarbate preparations for topical use.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2007Co-Authors: S. Lombardi Borgia, Peggy Schlupp, Wolfgang Mehnert, Monika Schäfer-kortingAbstract:Reconstructed human epidermis is a useful tool for in vitro skin absorption studies of chemical compounds. If this may hold true also for topical dermatics, we investigated the glucocorticoid Prednicarbate applied by two sets (innovator and generic) of cream, ointment and fatty ointment using the commercially available EpiDerm™ model. Moreover, stability and local tolerability of the preparations as well as drug release were studied, to estimate an influence on Prednicarbate absorption and metabolism. While release ranked in the order cream < fatty ointment < ointment for both sets of preparations, Prednicarbate penetration and permeation of the EpiDerm model did not. Less PC uptake observed with the generic ointment and fatty ointment appeared to be linked to impaired enzymatic ester cleavage within the tissue. Thus with drugs subject to skin metabolism, cutaneous uptake is not to be derived from drug release studies, yet has to be studied experimentally with viable skin or reconstructed human epidermis.
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The impact of skin viability on drug metabolism and permeation -- BSA toxicity on primary keratinocytes.
Toxicology in vitro : an international journal published in association with BIBRA, 2005Co-Authors: Annekathrin Haberland, Burkhard Kleuser, Hans Christian Korting, C. Santos Maia, S. Schreiber, M.k. Rübbelke, Martin Schaller, I. Schimke, Monika Schäfer-kortingAbstract:For testing cutaneous absorption of drugs, ingredients of cosmetics and also for risk assessment of industrial compounds predictable in vitro test protocols are under investigation using excised skin or reconstructed human epidermis. Since the metabolizing enzymes expressed by viable skin can influence the absorption behaviour of substances by changing their structure and thereby their physicochemical characteristics, the metabolic capacity should be considered in the design of the test protocols of compounds susceptible to metabolism. Then data, generated using viable reconstructed epidermis may reflect the in vivo situation. Interestingly, bovine serum albumin (BSA) commonly used in receptor media in permeation studies to facilitate solubility of highly lipophilic substances strongly inhibited the metabolism of topically applied Prednicarbate in reconstructed epidermis. Here, we show that 5% BSA is toxic to reconstructed epidermis and keratinocytes which was consistent with the earlier findings. While media toxicity (deficiency media) was at least partly the cause of both apoptotic and necrotic processes in keratinocytes, BSA only slightly increased the rate of necrotic cells. Moreover, caspase inhibitors did not reduce BSA toxicity. Yet, the results show that BSA toxicity on keratinocytes has to be carefully considered if this protein is used in permeation studies with reconstructed epidermis.
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Glucocorticoid entrapment into lipid carriers — characterisation by parelectric spectroscopy and influence on dermal uptake
Journal of controlled release : official journal of the Controlled Release Society, 2004Co-Authors: R. Sivaramakrishnan, Hans Christian Korting, Wolfgang Mehnert, C. Nakamura, K.d. Kramer, Monika Schäfer-kortingAbstract:Topical glucocorticoids such as betamethasone 17-valerate (BMV) and Prednicarbate (PC) are an important therapeutic option in atopic eczema. To reduce the risk of dermal atrophy, we aimed at BMV incorporation into solid lipid nanoparticles (SLN) for epidermal targeting using various lipids and emulsifiers corresponding to previous work on PC. Cutaneous absorption into excised human skin was compared to the one with a cream. While Compritol-based particles increased BMV uptake about fourfold we failed, however, to obtain epidermal targeting. To obtain insight into the location of active substance relative to the carrier, we used the recently optimised method of parelectric spectroscopy (PS). In fact, we were able to study electric dipole movements in the broad field of a frequency span from 0.1 to 100 MHz demonstrating that glucocorticoids are attached to the particle surface but are not incorporated into the lipid matrix. With BMV, the loading capacity of the particle surface lies clearly below the usual concentration of 0.1% which is not the case with PC. An adequate association of drug and carrier is essential for epidermal targeting. Parelectric spectroscopy provides insight into the interaction between drug and lipidic carrier.
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Transcriptional activity of potent glucocorticoids: relevance of glucocorticoid receptor isoforms and drug metabolites.
Skin pharmacology and applied skin physiology, 2003Co-Authors: I. Spika, Burkhard Kleuser, Hans Christian Korting, Stefanie Hammer, Monika Schäfer-kortingAbstract: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.
Jivaldo Do Rosário Matos - One of the best experts on this subject based on the ideXlab platform.
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Inclusion of Prednicarbate in the SBA-15 silica
Journal of Thermal Analysis and Calorimetry, 2015Co-Authors: Hélio Salvio Neto, Flávio Machado De Souza Carvalho, Gabriel Lima Barros De Araujo, Santos Leandro L, I.c. Cosentino, Jivaldo Do Rosário MatosAbstract:The present work describes the development and characterization of a nanostructured mesoporous SBA-15 silica loaded with Prednicarbate, a corticosteroid widely used in the treatment for atopic dermatitis, and the assessment of its in vitro release profile in comparison with a conventional cream formulation. The inclusion of Prednicarbate in the SBA-15 pores was confirmed by the respective 24 and 16 % decrease in the surface area (SBET) and mesopores volume (V), in combination with supporting data obtained by thermal analysis (TG and DSC), FTIR spectroscopy, X-ray diffraction, and elemental analysis. Additionally, it has been shown through X-ray diffraction and DSC that the encapsulated molecules remain in an amorphous state, and the protective function of the loading was demonstrated through thermogravimetry by the decrease in the rate of the thermal decomposition reaction of the drug-loaded material (Δm600–850 °C). Finally, the HPLC–MS/MS method developed was proven to be precise and accurate for the determination of Prednicarbate in the receiving fluid samples collected during the in vitro release test using Franz diffusion cells.
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Compatibility and decomposition kinetics studies of Prednicarbate alone and associated with glyceryl stearate
Journal of Thermal Analysis and Calorimetry, 2010Co-Authors: Hélio Salvio Neto, Jivaldo Do Rosário MatosAbstract:In this work, TG/DTG and DSC techniques were used to the determination of thermal behavior of Prednicarbate alone and associated with glyceryl stearate excipient (1:1 physical mixture). TG/DTG curves obtained for the binary mixture showed a reduction of approximately 37 °C to the thermal stability of drug (\( T_{{{\text{d}}m/{\text{d}}t = 0\,{\text{DTG}}}}^{\text{Max}} \)). The disappearance of stretching band at 1280 cm−1 (νas C–O, carbonate group) and the presence of streching band with less intensity at 1750 cm−1 (νs C–O, ester group) in IR spectrum obtained to the binary mixture submitted at 220 °C, when compared with IR spectrum of drug submitted to the same temperature, confirmed the chemical interaction between these substances due to heating. Kinetics parameters of decomposition reaction of Prednicarbate were obtained using isothermal (Arrhenius equation) and non-isothermal (Ozawa) methods. The reduction of approximately 45% of activation energy value (Ea) to the first step of thermal decomposition reaction of drug in the 1:1 (mass/mass) physical mixture was observed by both kinetics methods.
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Thermal analysis of Prednicarbate and characterization of thermal decomposition product
Journal of Thermal Analysis and Calorimetry, 2009Co-Authors: Hélio Salvio Neto, Fábio Alessandro Proença Barros, Flávio Machado De Souza Carvalho, Jivaldo Do Rosário MatosAbstract:In the present work, the thermal behavior of Prednicarbate was studied using DSC and TG/DTG. The solid product remaining at the first decomposition step of the drug was isolated by TG, in air and N2 atmospheres and was characterized using LC-MS/MS, NMR, and IR spectroscopy. It was found that the product at the first thermal decomposition step of Prednicarbate corresponds to the elimination of the carbonate group bonding to C17, and a consequent formation of double bond between C17 and C16. Structure elucidation of this degradation product by spectral data has been discussed in detail.
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Thermal analysis and compatibility studies of Prednicarbate with excipients used in semi solid pharmaceutical form
Journal of Thermal Analysis and Calorimetry, 2009Co-Authors: H. Salvio Neto, Cs. Novák, Jivaldo Do Rosário MatosAbstract:Differential Scanning Calorimetry (DSC), thermogravimetry/derivative thermogravimetry (TG/DTG) and infrared spectroscopy (IR) techniques were used to investigate the compatibility between Prednicarbate and several excipients commonly used in semi solid pharmaceutical form. The thermoanalytical studies of 1:1 (m/m) drug/excipient physical mixtures showed that the beginning of the first thermal decomposition stage of the Prednicarbate (Tonset value) was decreased in the presence of stearyl alcohol and glyceryl stearate compared to the drug alone. For the binary mixture of drug/sodium pirrolidone carboxilate the first thermal decomposition stage was not changed, however the DTG peak temperature (Tpeak DTG) decreased. The comparison of the IR spectra of the drug, the physical mixtures and of the thermally treated samples confirmed the thermal decomposition of Prednicarbate. By the comparison of the thermal profiles of 1:1 Prednicarbate:excipients mixtures (methylparaben, propylparaben, carbomer 940, acrylate crosspolymer, lactic acid, light liquid paraffin, isopropyl palmitate, myristyl lactate and cetyl alcohol) no interaction was observed.
Martina Kerscher - One of the best experts on this subject based on the ideXlab platform.
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Prednicarbate activity and benefit risk ratio in relation to other topical glucocorticoids
Clinical Pharmacology & Therapeutics, 1993Co-Authors: H. C. Korting, Martina Kerscher, Susanne Lenhard, Monika SchaferkortingAbstract: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-valer-ate (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.
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Prednicarbate activity and benefit/risk ratio in relation to other topical glucocorticoids
Clinical pharmacology and therapeutics, 1993Co-Authors: Monika Schäfer-korting, Hans Christian Korting, Martina Kerscher, Susanne LenhardAbstract: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-valer-ate (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.
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Topical glucocorticoids of the non-fluorinated double-ester type. Lack of atrophogenicity in normal skin as assessed by high-frequency ultrasound.
Acta dermato-venereologica, 1992Co-Authors: Martina Kerscher, Hans Christian KortingAbstract:With the advent of non-fluorinated double esters the spectrum of topical dermatotherapy with glucocorticoids seems to have broadened to include safer congeners. To assess the atrophogenicity potential of glucocorticoids, high-frequency ultrasound has been proposed. In a comparative trial using the DUB 20 system, 24 healthy volunteers applied hydrocortisone aceponate, the corresponding vehicle, Prednicarbate ointment and betamethasone-17-valerate ointment over a period of 6 weeks. While both hydrocortisone aceponate and Prednicarbate ointment induced no significant reduction in skin thickness, the onset of epidermal-dermal thinning with betamethasone-17-valerate was early and the extent marked. These findings imply an increased therapeutic index with the non-fluorinated double esters.
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0 25 Prednicarbate cream and the corresponding vehicle induce less skin atrophy than 0 1 betamethasone 17 valerate cream and 0 05 clobetasol 17 propionate cream
European Journal of Clinical Pharmacology, 1992Co-Authors: H. C. Korting, D. Vieluf, Martina KerscherAbstract:The atrophogenic potential of medium-potent topical glucocorticoids is still controversial. In a double-blind controlled trial 24 healthy volunteers either applied 0.25% Prednicarbate cream or the corresponding vehicle to one and 0.1% betamethasone-17-valerate cream or 0.05% clobetasol-17-propionate cream to the other forearm twice daily. Skin thickness was regularly assessed during the six week period of application and for further three weeks thereafter, using both the B- and A-mode of a 20 MHz ultrasound scanner.
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0.25% Prednicarbate cream and the corresponding vehicle induce less skin atrophy than 0.1% betamethasone-17-valerate cream and 0.05% clobetasol-17-propionate cream.
European journal of clinical pharmacology, 1992Co-Authors: Hans Christian Korting, D. Vieluf, Martina KerscherAbstract:The atrophogenic potential of medium-potent topical glucocorticoids is still controversial. In a double-blind controlled trial 24 healthy volunteers either applied 0.25% Prednicarbate cream or the corresponding vehicle to one and 0.1% betamethasone-17-valerate cream or 0.05% clobetasol-17-propionate cream to the other forearm twice daily. Skin thickness was regularly assessed during the six week period of application and for further three weeks thereafter, using both the B- and A-mode of a 20 MHz ultrasound scanner.
Katharina Lange - One of the best experts on this subject based on the ideXlab platform.
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Skin Penetration and Metabolism of Topical Glucocorticoids in Reconstructed Epidermis and in Excised Human Skin
Pharmaceutical Research, 1999Co-Authors: Anja Gysler, Katharina Lange, Burkhard Kleuser, Hans Christian Korting, Wolfgang Sippl, Hans-dieter Höltje, Monika Schäfer-kortingAbstract: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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Skin penetration and metabolism of topical glucocorticoids in reconstructed epidermis and in excised human skin.
Pharmaceutical research, 1999Co-Authors: Anja Gysler, Katharina Lange, Burkhard Kleuser, Hans Christian Korting, Wolfgang Sippl, Hans-dieter Höltje, Monika Schäfer-kortingAbstract: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.
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Prednicarbate Versus Conventional Topical Glucocorticoids: Pharmacodynamic Characterization In Vitro
Pharmaceutical Research, 1997Co-Authors: Katharina Lange, Anja Gysler, Michael Bader, Burkhard Kleuser, Hans Christian Korting, Monika Schäfer-kortingAbstract: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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Prednicarbate Biotransformation in Human Foreskin Keratinocytes and Fibroblasts
Pharmaceutical Research, 1997Co-Authors: Anja Gysler, Katharina Lange, Hans Christian Korting, Monika Schäfer-kortingAbstract: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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Prednicarbate Versus Conventional Topical Glucocorticoids: Pharmacodynamic Characterization In Vitro
Pharmaceutical research, 1997Co-Authors: Katharina Lange, Anja Gysler, Michael Bader, Burkhard Kleuser, Hans Christian Korting, Monika Schäfer-kortingAbstract: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.