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At least 1,081 records · Page 60Linked to original sources
PubMed1988

Rapid metabolic inactivation of tipredane, a structurally novel topical steroid.

[3H]Tipredane ([3H]TP), [3H]triamcinolone acetonide ([ 3H]TAAC), [3H]hydrocortisone ([3H]HC), and [3H]betamethasone-17 alpha-valerate ([3H]BMV), each at a concentration of 1 microM, were separately incubated with the 10,000 g supernatant fraction of the liver and skin homogenates of humans, rats and mice (BMV was studied only in human liver). Sequential samples were taken for up to 1 h during each incubation. The radioactivity in each sample was extracted with methanol, and the methanolic extracts were analyzed by high performance liquid chromatography. Among the four compounds studied, [3H]TP was most rapidly biotransformed by the liver preparations of the three species. The rates of in vitro biotransformation of TP were 2.5-30 times faster than those of TAAC, HC and BMV. In the human liver preparation, the rates of biotransformation were in the order of: TP greater than TAAC greater than HC = BMV. In the mouse and rat liver preparations, the orders were: TP greater than TAAC greater than HC and TP greater than HC greater than TAAC, respectively. In the skin preparations, little, if any, biotransformation of [3H]TP and [3H]TAAC was observed in any of the species studied; however, [3H]HC underwent a slow, steady biotransformation in the skin preparations of humans and rats but not of mice. [3H]TP was biotransformed by the liver preparations of all three species to numerous metabolites, thirteen of which have been identified. The biotransformation reactions included: (1) sulfoxidation; (2) elimination of either one or both alkylthio groups; and (3) hydroxylation of the steroid nucleus. Some metabolites were synthesized and tested for glucocorticoid receptor binding and anti-inflammatory activities; all were found to be much less potent than TP. The observed separation of local anti-inflammatory activity from systemic side effects of TP is most probably due to its rapid metabolic inactivation; the liver, rather than the skin, is mainly responsible for the metabolic inactivation of TP.

Androstadienes↗
PubMed1996

On-line post-column photochemical derivatization in liquid chromatographic--diode-array detection analysis of binary drug mixtures.

HPLC methods were developed for the analysis of pharmaceutical creams containing binary drug mixtures (betamethasone valerate-chlorocresol; hydrocortisone-miconazole nitrate; desonide pivalate-chlorhexidine; dexamethasone-clotrimazole; triamcinolone acetonide-econazole nitrate). The chromatographic separations were performed on C-18 and cyano columns under reversed-phase conditions. A post-column on-line photochemical reactor (irradiation at 254 nm) was arranged between the analytical column and the diode-array detector to enhance the performance of the method. Two UV spectra (photoreactor on and off) were obtained for each analyte and these additional sources of information proved to be useful for the unambiguous identification of the various analytes. The method was applied to the quality control of commercial creams using a solid-phase extraction procedure for the sample clean-up.

Administration, Topical↗
PubMed1992

Quantifying anti-inflammatory agents' potency by measurement of response to dinitrochlorobenzene challenge.

Classical assays of topical corticosteroid potency based on the induction of vasoconstriction are unsatisfactory for a number of reasons. These include the doubtful relevance of vasoconstriction to immune inflammation, and more importantly, the inability to compare non-steroidal agents with corticosteroids. Here we describe a simple assay in which the inhibitory effect of agents upon delayed type hypersensitivity response to dinitrochlorobenzene can be quantified by measurements of reaction as skinfold thickness with Harpenden callipers. Using this system we have confirmed the greater potency of clobetasol propionate (Dermovate) compared with betamethasone valerate (Betnovate), but the evidence for an inhibitory effect of topical cyclosporin (10% cream) compared with base on this response is less convincing.

Administration, Topical↗
PubMed2006

The cannabinoid CB2 receptor inverse agonist JTE-907 suppresses spontaneous itch-associated responses of NC mice, a model of atopic dermatitis.

JTE-907, N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide, is a selective cannabinoid CB2 receptor antagonist/inverse agonist. The anti-pruritic activity of JTE-907 was studied in NC mice with chronic dermatitis, a model of atopic dermatitis. The oral dose of JTE-907 (1 and 10 mg/kg/day), an immunosuppressant agent tacrolimus (1 mg/kg/day) and a glucocorticoid betamethasone 17-valerate (1 mg/kg/day) for 20 days suppressed the spontaneous scratching and cutaneous nerve activity of NC mice. JTE-907 (10, but not 1, mg/kg) and tacrolimus, but not betamethasone, tended to alleviate the dermatitis. Betamethasone inhibited the body weight gain. These results suggest that JTE-907 suppresses spontaneous itch-associated responses of NC mice without adverse effects such as weight loss.

Administration, Oral↗
PubMed2006

Biosynthesis and native granule characteristics of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) in Delftia acidovorans.

The ability of Delftia acidovorans to incorporate a broad range of 3-hydroxyvalerate (3HV) monomers into polyhydroxyalkanoate (PHA) copolymers was evaluated in this study. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [P(3HB-co-3HV)] containing 0-90 mol% of 3HV was obtained when a mixture of sodium 3-hydroxybutyrate and sodium valerate was used as the carbon sources. Transmission electron microscopy analysis revealed an interesting aspect of the P(3HB-co-3HV) granules containing high molar ratios of 3HV whereby, the copolymer granules were generally larger than those of poly(3-hydroxybutyrate) [P(3HB)] granules, despite having almost the same cellular PHA contents. The large number of P(3HB-co-3HV) granules occupying almost the entire cell volume did not correspond to a higher amount of polymer by weight. This indicated that the granules of P(3HB-co-3HV) contain polymer chains that are loosely packed and therefore have lower density than P(3HB) granules. It was also interesting to note that a decrease in the length of the side chain from 3HV to 4-hydroxybutyrate (4HB) corresponded to an increase in the density of the respective PHA granules. The presence of longer side chain monomers (3HV) in the PHA structure seem to exhibit steric effects that prevent the polymer chains in the granules from being closely packed. The results reported here have important implications on the maximum ability of bacterial cells to accumulate PHA containing monomers with longer side chain length.

Centrifugation, Density Gradient↗
PubMed2005

Clinical studies of a new vehicle formulation for topical corticosteroids in the treatment of psoriasis.

Topical corticosteroids have been the mainstay of topical anti-inflammatory therapy of psoriasis and are available in different treatment strengths or doses and various formulations or vehicles. Traditional formulations have included ointments, creams, and lotions. More recently, the mid-potency corticosteroid betamethasone valerate (BMV) and the ultra-high-potency corticosteroid clobetasol propionate (CP) have become available in a novel, thermolabile, low-residue foam vehicle for topical application. This review examines recent clinical studies on efficacy and safety of these two new formulations, BMV 0.12% foam (Luxiq; Connetics Corp, Palo Alto, Calif) and CP 0.05% foam (OLUX, Connetics Corp), as treatments for scalp and nonscalp psoriasis. The studies demonstrated that BMV foam and CP foam are safe and effective treatments for psoriasis affecting scalp and nonscalp regions of the body. BMV foam and CP foam were absorbed more rapidly and demonstrated greater total absorption than their respective comparison formulations, namely BMV lotion and CP solution. The foam vehicle also appears to be associated with better compliance and improvements in quality of life. The unique nature of the foam vehicle, together with the positive findings of in vitro studies suggest these new foam formulations may expand the options currently available for combination therapy.

Administration, Cutaneous↗
PubMed1999

A new approach for determination of neuropathy target esterase activity.

Neuropathy target esterase (NTE) was shown to be an excellent biochemical marker for screening of organophosphates (OPs) with respect to their ability to result in organophosphate induced delayed neurotoxicity (OPIDN). This paper describes a new biosensor approach to the analysis of NTE and its inhibitors. The method is based on the combination of NTE enzymatic hydrolysis of phenyl valerate (PV) with phenol detection by the Clark-type oxygen electrode modified by immobilized tyrosinase. The validity of this biosensor method is confirmed by the facts that the calibration curves for NTE obtained by colorimetric and flow-through electrochemical methods were nearly identical and the titration of NTE by test inhibitor mipafox was shown to yield the same pI50 values. The developed electrochemical methods can be considered as a promising approach both for serial express NTE analysis and for kinetic characteristics of NTE.

Animals↗
PubMed1999

Determination of polyhydroxyalkanoates in activated sludge by ion chromatographic and enzymatic methods.

Two new detection methods for the determination of poly-beta-hydroxybutyrate (PHB) and -valerate (PHV) are described. Both methods are based on depolymerization of PHB/PHV to 3-hydroxybutyrate (3HB) and 3-hydroxyvalerate (3HV). Depolymerization was achieved by either propanolic or hydrolytic digestion. Propanolic digestion transformed commercial PHB/PHV stoichiometrically into 3HB/3HV and yielded apparently complete recoveries of bacterial PHB/PHV from activated sludge. Hydrolytic digestion was suitable only for PHB determination. For quantification of 3HB and 3HV directly from digested sludge, a method based on ion-exchange chromatography and conductivity detection was developed (IC-method). Alternatively, the total of 3HB and 3HV was quantified using a commercial enzymatic test kit and colorimetric detection (enzyme method). Both detection methods are easier to perform than previous methods and are suitable for complex matrices such as activated sludge. The IC-method is recommended for high sample throughputs or if distinction between PHB and PHV is essential. Enzymatic detection is recommended if a few samples per day have to be measured immediately or if an ion chromatograph is unavailable.

1-Propanol↗
PubMed1997

A comparison of subjective and objective measures of reduction of psoriasis with the use of ultrasound, reflectance colorimetry, computerized video image analysis, and nitric oxide production.

BACKGROUND: Studies of antipsoriatic therapy often rely on subjective scoring. Objective measures have been developed but have not previously been compared with subjective scoring. OBJECTIVE: Our purpose was to compare subjective and objective measures of reduction of psoriasis with topical therapy. METHODS: A 2-week, double-blind, left-to-right comparative trial of betamethasone valerate against white soft paraffin was performed in 12 patients. The subjective scores were erythema, elevation, scale, and a composite total. Objective measures were nitric oxide production measured by chemiluminescence; erythema reflectance; ultrasound scan for thickness, scale, and echo-poor zone; and computerized image analysis of video images. RESULTS: Subjective and objective measures had similar power to detect therapeutic effect. The subjective measures showed greater variation and relatively overestimated improvement. There was correlation between measures and estimates for area, redness, and thickness. Nitric oxide production was the most powerful objective measure. CONCLUSION: Thickness determined by ultrasound scan and nitric oxide production are useful measures of reduction of psoriasis, which lend themselves to more powerful statistical tests than subjective interval data.

Administration, Topical↗
PubMed1999

Analysis of chromameter results obtained from corticosteroid-induced skin blanching assay: comparison of visual and chromameter data.

In a Guidance document, the American FDA recommends the use of a Minolta chromameter rather than the human eye for the quantitative assessment of the pharmacodynamic blanching response produced by topical application of corticosteroids. The purpose of this study was to compare the appropriateness of the human eye and two models of chromameter for the estimation of skin blanching, in terms of the quality of the data generated by each method. The corticosteroid-induced skin blanching from four different betamethasone 17-valerate cream formulations was compared in a typical human skin blanching trial. The optimized assay methodology routinely practised in our laboratories was utilized. The blanching responses were assessed visually by three trained, independent observers and recorded by two chromameters (Minolta model CR-200 and model CR-300). The topical availability of the four creams was determined using visual scoring and chromameter measurements. All data were manipulated in such a manner as to produce a blanching response versus time profile from which AUBC analysis could be performed. Good correlation was observed between the visual assessments made by three independent observers. In contrast, moderate correlation was determined between visual, CR-200 and CR-300 measurements. Surprisingly, no direct linear relationship between the AUBCs produced by the two chromameters was observed indicating that the quality of the data obtained from the two instruments may not be equal. This investigation also indicated that the use of the chromameter is not completely objective. Visual scoring and chromameter measurement produce data sets that differ in quality. Each procedure needs to be validated and investigators have to be trained for both visual assessment and the operation of the chromameter, particularly with regard to the manipulation of the measuring head of the instrument.

Administration, Topical↗
PubMed2000

Mechanism of nitroalkane oxidase: 2. pH and kinetic isotope effects.

Nitroalkane oxidase catalyzes the oxidation of nitroalkanes to aldehydes or ketones with production of nitrite and hydrogen peroxide. pH and kinetic isotope effects with [1, 1-(2)H(2)]nitroethane have been used to study the mechanism of this enzyme. The V/K(ne) pH profile is bell-shaped. A group with a pK(a) value of about 7 must be unprotonated and one with a pK(a) value of 9.5 must be protonated for catalysis. The lower pK(a) value is seen also in the pK(is) profile for the competitive inhibitor valerate, indicating that nitroethane has no significant external commitments to catalysis. The (D)(V/K)(ne) value is pH-independent with a value of 7.5, whereas the (D)V(max) value increases from 1.4 at pH 8.2 to a limiting value of 7.4 below pH 5. The V(max) pH profile decreases at low and high pH, with pK(a) values of 6.6 and 9.5, respectively. Imidazole, which activates the enzyme, affects the V(max) but not the V/K(ne) pH profile. In the presence of imidazole at pH 7 the (D)V(max) value increases to a value close to the intrinsic value, consistent with cleavage of the carbon-hydrogen bond of the substrate being fully rate-limiting for catalysis in the presence of imidazole.

Deuterium↗
PubMed1998

13C-NMR study of propionate metabolism by sludges from bioreactors treating sulfate and sulfide rich wastewater.

Applications of nuclear magnetic resonance (NMR) to study a variety of physiological and biochemical aspects of bacteria with a role in the sulfur cycle are reviewed. Then, a case-study of high resolution 13C-NMR spectroscopy on sludges from bioreactors used for treating sulfate and sulfide rich wastewaters is presented. 13C-NMR was used to study the effect of sulfate and butyrate on propionate conversion by mesophilic anaerobic (methanogenic and sulfate reducing) granular sludge and microaerobic (sulfide oxidizing) flocculant sludge. In the presence of sulfate, propionate was degraded via the randomising pathway in all sludge types investigated. This was evidenced by scrambling of [3-13C]propionate into [2-13C]propionate and the formation of acetate equally labeled in the C1 and C2 position. In the absence of sulfate, [3-13C]propionate scrambled to a lesser extend without being degraded further. Anaerobic sludges converted [2,3-13C]propionate partly into the higher fatty acid 2-methyl[2,3-13C]butyrate during the simultaneous degradation of [2,3-13C]propionate and butyrate. [4,5-13C]valerate was also formed in the methanogenic sludges. Up to 10% of the propionate present was converted via these alternative degradation routes. Labeled butyrate was not detected in the incubations, suggesting that reductive carboxylation of propionate does not occur in the sludges.

Biodegradation, Environmental↗
PubMed1997

Evaluation of the proposed FDA pilot dose-response methodology for topical corticosteroid bioequivalence testing.

PURPOSE: The American FDA has recently released a Guidance document for topical corticosteroid bioequivalence testing. The purpose of this study was to evaluate the recommendations of this document for appropriateness. The new specifications require a dose-vasoconstriction response estimation by the use of a Minolta chromameter in a preliminary pilot study to determine the parameters for use in a pivotal bioequivalence study. METHODS: The visually-assessed human skin balancing assay methodology routinely practiced in our laboratories was modified to comply with the requirements of the pilot study so that visual and chromameter data could be compared. Two different cream formulations, each containing 0.12% betamethasone 17-valerate, were used for this comparison. RESULTS: Visual data showed the expected rank order of AUC values for most dose durations whereas the chromameter data did not show similar results. The expected rank order of AUC values for both chromameter and visual data was not observed at very short dose durations. In fitting the data to pharmacodynamic models, equivalent goodness of fit criteria were obtained when several different parameter estimates were used in the model definition, however the visual data were best described by the sigmoid Emax model while the chromameter data were best described by the simple Emax model. CONCLUSIONS: The Emax values predicted by the models were close to the observed values for both data sets and in addition, excellent correlation between the AUC values and the maximum blanching response (Rmax) (r > 0.95) was noted for both methods of assessment. The chromameter ED50 values determined in this study were approximately 2 hours for both preparations. At this dose duration the instrument would not be sensitive enough to distinguish between weak blanching responses and normal skin for bioequivalence assessment purposes.

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↗
PubMed1999

Skin penetration and metabolism of topical glucocorticoids in reconstructed epidermis and in excised human skin.

PURPOSE: To investigate pharmacokinetic differences between the nonhalogenated 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 (PI7EC), 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 concentration about 6-fold may contribute to its lower tolerance when compared to PC.

Administration, Topical↗
PubMed2001

Efficacy of corticosteroids in acute experimental irritant contact dermatitis?

BACKGROUND/AIMS: Topical corticoids are used to treat irritant contact dermatitis (ICD) in humans. However, their clinical efficacy remains sub judice. This study was designed to assess the efficacy of low- and medium-potency corticosteroids on irritant dermatitis. METHODS: We induced an acute ICD via open application of sodium lauryl sulphate (SLS) on the hands of subjects. The dorsal side of hands was irritated with 10% SLS five times in one day. Once on day 1 and twice daily on days 2-5, 1% hydrocortisone, 0.1% betamethasone-17-valerate and vehicle cream (petrolatum) were applied subsequently. Visual grading, bioengineering techniques and squamometry were used to quantify skin response. RESULTS: Corticosteroids were found ineffective in treating the surfactant-induced irritant dermatitis when compared with the vehicle and with the untreated control. CONCLUSION: The counterintuitive result (in a relatively realistic and robust model) should be interpreted with caution until verified with other irritants of varying physicochemical properties.

Adult↗
PubMed1969

Microbiological degradation of bile acids. Ring A cleavage and 7alpha, 12alpha-dehydroxylation of cholic acid by Arthrobacter simplex.

The metabolism of cholic acid by Arthrobacter simplex was investigated. This organism effected both ring a cleavage and elimination of the hydroxyl groups at C-7 and C-12 and gave a new metabolite, (4R)-4-[4alpha-(2-carboxyethyl)-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-1beta-yl]valeric acid, which was isolated and identified through its partial synthesis. A degradative pathway of cholic acid into this metabolite is tentatively proposed, and the possibility that the proposed pathway could be extended to the cholic acid degradation by other microorganisms besides A. simplex is discussed. The possibility that the observed reactions in vitro could occur during the metabolism of bile acids in vivo is considered.

Arthrobacter↗
PubMed1976

Microbiological degradation of bile acids. The conjugation of a certain cholic acid metabolite with amino acids in Corynebacterium equi.

1. (4R)-4[4alpha-(2-Carboxyethyl)-3aalpha-hexahydro-7abeta-methyl-5-oxoindan-1beta-yl]valeric acid (II) could not be utilized by Arthrobacter simplex, even though the acid was one of the metabolites formed from cholic acid (I) by this organism. Therefore the further degradation of the acid (II) by Corynebacterium equi was investigated to identify the intermediates involved in the cholic acid degradation. 2. The organism, cultured in a medium containing the acid (II) as the sole source of carbon, produced unexpected metabolites, the conjugates of this original acid (II) with amino acids or their derivatives, although the yield was very low. These new metabolites were isolated and identified by chemical synthesis as the Na-((4R)-4-[4alpha-(2-carboxyethyl)-3a alpha-hexahydro-7a beta-methyl-5-oxoindan-1 beta-yl]-valeryl) derivatives of L-alanine, glutamic acid, O-acetylhomoserine and glutamine, i.e. compounds (IIIa), (IIIb), (IIId) respectively. 3. The possibility that the bacterial synthetic reaction observed in the acid (II) metabolism with C. equi is analogous to peptide conjugation known in both animals and higher plants is discussed. A possible mechanism for this bacterial conjugation is also considered.

Alanine↗